Journal of Cachexia Sarcopenia and Muscle

Journal of Cachexia Sarcopenia and Muscle

Association of change in muscle mass assessed by D3‐creatine dilution with changes in grip strength and walking speed

17-10-2019 – Kate A. Duchowny, Katherine E. Peters, Steven R. Cummings, Eric S. Orwoll, Andrew R. Hoffman, Kristine E. Ensrud, Jane A. Cauley, William J. Evans, Peggy M. Cawthon, for the Osteoporotic Fractures in Men (MrOS) Study Research Group

Abstract
Background
Muscle mass declines with age. However, common assessments used to quantify muscle mass are indirect. The D3‐creatine (D3Cr) dilution method is a direct assessment of muscle mass; however, longitudinal changes have not been examined in relation to changes in other measures of muscle mass, strength, and performance.
Methods
A convenience sample of 40 men from the Osteoporotic Fractures in Men Study (mean age = 83.3 years, standard deviation = 3.9) underwent repeat assessment of D3Cr muscle mass, dual‐energy X‐ray absorptiometry (DXA) lean mass, grip strength, and walking speed at two time points approximately 1.6 years apart (2014–2016). One‐sample t‐tests and Pearson correlations were used to examine changes in DXA total body lean mass, DXA appendicular lean mass/height2, DXA appendicular lean mass/weight, D3Cr muscle mass, D3Cr muscle mass/weight, grip strength, walking speed, and weight.
Results
D3‐creatine muscle mass, D3Cr muscle mass/weight, grip strength, and walking speed all significantly declined (all P < 0.01). The change in DXA measures of lean mass was moderately correlated with changes in D3Cr muscle mass. There was no significant correlation between the change in DXA measures of lean mass and change in walking speed (all P > 0.05). The change in D3Cr muscle mass/weight was moderately correlated with change in walking speed (r = 0.33, P < .05). The change in grip strength was weakly correlated with the change in DXA measures of lean mass and D3Cr muscle mass (r = 0.19–0.32).
Conclusions
The results of our study provide new insights regarding the decline in muscle strength and D3Cr muscle mass. The D3Cr method may be a feasible tool to measure declines in muscle mass over time.

Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men

30-09-2019 – Nima Gharahdaghi, Supreeth Rudrappa, Matthew S. Brook, Iskandar Idris, Hannah Crossland, Claire Hamrock, Muhammad Hariz Abdul Aziz, Fawzi Kadi, Janelle Tarum, Paul L. Greenhaff, Dumitru Constantin‐Teodosiu, Jessica Cegielski, Bethan E. Phillips, Daniel J. Wilkinson, Nathaniel J. Szewczyk, Kenneth Smith, Philip J. Atherton

Journal Article

Abstract
Background
The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia), and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to short‐term RET remain poorly defined.
Methods
Eighteen non‐hypogonadal healthy older men, 65–75 years, were assigned in a random double‐blinded fashion to receive, biweekly, either placebo (P, saline, n = 9) or T (Sustanon 250 mg, n = 9) injections over 6 week whole‐body RET (three sets of 8–10 repetitions at 80% one‐repetition maximum). Subjects underwent dual‐energy X‐ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D2O), and breakdown (extrapolated).
Results
Testosterone adjuvant to RET augmented total fat‐free mass (P=0.007), legs fat‐free mass (P=0.02), and appendicular fat‐free mass (P=0.001) gains while decreasing total fat mass (P=0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross‐section area with RET occured to a greater extent in T (P < 0.05). Sum strength (P=0.0009) and maximal voluntary contract (e.g. knee extension at 70°) (P=0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13 ± 0.21%·day−1 vs. P: 1.34 ± 0.13%·day−1, P=0.0009) and absolute breakdown rates (T: 140.2 ± 15.8 g·day−1 vs. P: 90.2 ± 11.7 g·day−1, P=0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3 ± 1.4 g·day−1 vs. P: 1.9 ± 1.2 g·day−1, P=0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); m
RNA expression relating to T metabolism (androgen receptor: 1.4‐fold; Srd5a1: 1.6‐fold; AKR1C3: 2.1‐fold; and HSD17β3: two‐fold); insulin‐like growth factor (IGF)‐1 signalling IGF‐1Ea (3.5‐fold) and IGF‐1Ec (three‐fold) and myogenic regulatory factors; and the activity of anabolic signalling (e.g. m
TOR, AKT, and RPS6; P < 0.05) were all up‐regulated with T therapy. Only T up‐regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (1.41 ± 0.2‐fold, P=0.0002), in addition to peroxisome proliferator‐activated receptor‐γ co‐activator 1‐α m
RNA (1.19 ± 0.21‐fold, P=0.037).
Conclusions
Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while up‐regulating myogenic gene programming, myocellular translational efficiency and capacity, collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short‐term intervention to improve muscle mass/function in older non‐hypogonadal men.

Disease‐induced and treatment‐induced alterations in body composition in locally advanced head and neck squamous cell carcinoma

19-09-2019 – Anna C.H. Willemsen, Ann Hoeben, Roy I. Lalisang, Ardy Van Helvoort, Frederik W.R. Wesseling, Frank Hoebers, Laura W.J. Baijens, Annemie M.W.J. Schols

Journal Article

Abstract
Background
Chemoradiation or bioradiation treatment (CRT/BRT) of locally advanced head and neck squamous cell carcinoma (LAHNSCC) comes with high toxicity rates, often leading to temporary tube feeding (TF) dependency. Cachexia is a common problem in LAHNSCC. Yet changes in body composition and muscle weakness during CRT/BRT are underexplored. Strong evidence on the effect of TF on body composition during treatment is lacking. The aim of this cohort study was to assess (i) the relationship of fat‐free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, (ii) body composition in patients treated with chemoradiation (cisplatin) vs. bioradiation (cetuximab), and (iii) the effect of the current TF regime on body composition and muscle strength.
Methods
Locally advanced head and neck squamous cell carcinoma patients treated with CRT/BRT between January 2013 and December 2016 were included (n = 137). Baseline measurements of body composition (bioelectrical impedance analysis) and HGS were performed. Toxicity grades (Common Terminology Criteria for Adverse Events) were scored. In a subset of 69 patients, weight loss, body composition, and HGS were additionally assessed during and after CRT/BRT. TF was initiated according to the Dutch guidelines for malnutrition.
Results
In this cohort (68% male, mean age 59 ± 8 years), the incidence of baseline muscle wasting, defined as FFMI < P10, was 29%. Muscle wasting was present in 23 of 100 (23%) chemoradiation patients and 17 of 37 (46%) bioradiation patients (P = 0.009). Muscle‐wasted patients required more unplanned hospitalizations during CRT (P = 0.035). In the chemoradiation subset, dose‐limiting toxicity was significantly higher in wasted vs. non‐wasted patients (57% vs. 25%, P = 0.004). Median follow‐up was 32 months. Multivariate Cox regression analysis identified muscle wasting as independent unfavourable prognostic factor for overall survival hazard ratio 2.1 (95% CI 1.1–4.1), P = 0.022 and cisplatin as favourable prognostic factor hazard ratio 0.3 (95% CI 0.2–0.6), P = 0.001. Weight and HGS significantly decreased during CRT/BRT, −3.7 ± 3.5 kg (P < 0.001) and −3.1 ± 6.0 kg (P < 0.001), respectively. Sixty‐four per cent of the patients required TF 21 days (range 0–59) after CRT/BRT initiation. Total weight loss during CRT/BRT was significantly (P = 0.007) higher in the total oral diet group (5.5 ± 3.7 kg) compared with the TF group (3.0 ± 3.2 kg). Loss of FFM and HGS was similar in both groups.
Conclusions
In LAHNSCC patients undergoing CRT/BRT, FFMI < P10 is an unfavourable prognostic factor for overall survival, treatment toxicity, and tolerance. Patients experience significant weight and FFM loss during treatment. Current TF regime attenuates weight loss but does not overcome loss of muscle mass and function during therapy. Future interventions should consider nutritional intake and additional strategies specifically targeting metabolism, loss of muscle mass, and function.

Sarcopenia: A Time for Action. An SCWD Position Paper

15-09-2019 – Juergen Bauer, John E. Morley, Annemie M.W.J. Schols, Luigi Ferrucci, Alfonso J. Cruz‐Jentoft, Elsa Dent, Vickie E. Baracos, Jeffrey A. Crawford, Wolfram Doehner, Steven B. Heymsfield, Aminah Jatoi, Kamyar Kalantar‐Zadeh, Mitja Lainscak, Francesco Landi, Alessandro Laviano, Michelangelo Mancuso, Maurizio Muscaritoli, Carla M. Prado, Florian Strasser, Stephan Haehling, Andrew J.S. Coats, Stefan D. Anker

Journal Article

Abstract
The term sarcopenia was introduced in 1988. The original definition was a “muscle loss” of the appendicular muscle mass in the older people as measured by dual energy x‐ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC‐F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease‐related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age‐related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age‐related and disease‐related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life‐long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.

Differentially methylated gene patterns between age‐matched sarcopenic and non‐sarcopenic women

11-09-2019 – Lingxiao He, Praval Khanal, Christopher I. Morse, Alun Williams, Martine Thomis

Journal Article

Abstract
Background
Sarcopenia is characterized by progressive decreases in muscle mass, muscle strength, and muscle function with ageing. Although many studies have investigated the mechanisms of sarcopenia, its connection with epigenetic factors, such as DNA methylation, still remains poorly understood. The aim of this study was to explore sarcopenia‐related DNA methylation differences in blood samples between age‐matched sarcopenic and non‐sarcopenic older women.
Methods
A sarcopenic group (n = 24) was identified and selected from a set of 247 older Caucasian women (aged 65–80 years) based on cut‐off points of skeletal muscle index at 6.75 kg/m2 and grip strength at 26 kg (the lower quintile of grip strength in the set). A non‐sarcopenic group (n = 24) was created with a similar age distribution as that of the sarcopenic group. DNA methylation patterns of whole blood samples from both groups were analysed using Infinium Methylation
EPIC Bead
Chip arrays. Differentially methylated cytosin–phosphate–guanine sites (dm
Cp
Gs) were identified at a P value threshold of 0.01 by comparing methylation levels between the sarcopenic and non‐sarcopenic groups at each Cp
G site. dm
Cp
G‐related genes were annotated based on Homo sapiens hg19 genome build. The functions of these genes were further examined by GO and KEGG pathway enrichment analysis.
Results
The global methylation level of all analysed Cp
G sites (n = 788 074) showed no significant difference between the sarcopenic and non‐sarcopenic groups (0.812), while the average methylation level of dm
Cp
Gs (n = 6258) was significantly lower in the sarcopenic group (0.004). The sarcopenic group had significantly higher methylation levels in TSS200 (the region from transcription start site to 200 nucleotides upstream of the site) and lower methylation levels in gene body and 3UTR regions. In respect of Cp
G regions, Cp
G islands in promoters and some intragenic regions showed greater levels of methylation in the sarcopenic group. dm
Cp
G‐related KEGG pathways were mainly associated with muscle function, actin cytoskeleton regulation, and energy metabolism. Seven genes (HSPB1, PBX4, CNKSR3, ORMDL3, MIR10A, ZNF619, and CRADD) were found with the same methylation direction as previous studies of blood sample methylation during ageing. Fifty‐four genes were shared with previous studies of resistance training.
Conclusions
Our results improve understanding of epigenetic mechanisms of sarcopenia by identifying sarcopenia‐related DNA methylation differences in blood samples of older women. These methylation differences suggest underlying alterations of gene expression and pathway function, which can partially explain sarcopenia‐related muscular changes.

Signal regulatory protein alpha initiates cachexia through muscle to adipose tissue crosstalk

11-09-2019 – Jiao Wu, Jiangling Dong, Daniela Verzola, Keith Hruska, Giacomo Garibotto, Zhaoyong Hu, William E. Mitch, Sandhya S. Thomas

Journal Article

Abstract
Background
Muscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD.
Methods
We assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle‐specific or adipose tissue‐specific KO of SIRPα. Metabolic responses were confirmed in primary cultures of adipose cells.
Results
In mice with CKD, SIRPα expression was increased in WAT (three‐fold, P < 0.05), and this was associated with precursors of cachexia: ‘pathologic browning’, thermogenesis, and a two‐fold activation of protein kinase A (P < 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRPα global KO and CKD or acute diabetes experienced improved insulin signalling and activation of p
Akt plus ‘physiologic browning’ of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (P < 0.05) than did wild‐type mice with CKD. In muscle‐specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (P < 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose‐specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over two‐fold (P < 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRPα signalling are suggested by our findings that include increased SIRPα expression in muscle and adipose tissues (P < 0.05 vs. healthy controls) plus higher SIRPα levels in the serum of patients with CKD (2.4‐fold, P=0.000017 vs. healthy controls).
Conclusions
Our results show that SIRPα plays an important role as an anti‐insulin mediator regulating pathways to cachexia. In muscle‐specific SIRPα KO, changes in SIRPα serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRPα may prevent cachexia in patients with CKD or acute diabetes.

Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial

28-08-2019 – Ulrich T. Hacker, Dirk Hasenclever, Nicolas Linder, Gertraud Stocker, Hyun‐Cheol Chung, Yoon‐Koo Kang, Markus Moehler, Harald Busse, Florian Lordick

Journal Article

Abstract
Background
Body fat and/or muscle composition influences prognosis in several cancer types. For advanced gastric and gastroesophageal junction cancer, we investigated which body composition parameters carry prognostic information beyond well‐established clinical parameters using robust model selection strategy such that parameters identified can be expected to generalize and to be reproducible beyond our particular data set. Then we modelled how differences in these parameters translate into survival outcomes.
Methods
Fat and muscle parameters were measured on baseline computed tomography scans in 761 patients with advanced gastric or gastroesophageal junction cancer from the phase III EXPAND trial, undergoing first‐line chemotherapy. Cox regression analysis for overall survival (OS) and progression‐free survival (PFS) included body composition parameters and clinical prognostic factors. All continuous variables were entered linearly into the model as there was no evidence of non‐linear prognostic impact. For transferability, the final model included only parameters that were picked by Bayesian information criterion model selection followed by bootstrap analysis to identify the most robust model.
Results
Muscle and fat parameters formed correlation clusters without relevant between‐cluster correlation. Mean muscle attenuation (MA) clusters with the fat parameters. In multivariate analysis, MA was prognostic for OS (P < 0.0001) but not for PFS, while skeletal muscle index was prognostic for PFS (P = 0.02) but not for OS. Worse performance status Eastern Cooperative Oncology Group (ECOG 1/0), younger age (on a linear scale), and the number of metastatic sites were strong negative clinical prognostic factors for both OS and PFS. MA remained in the model for OS (P = 0.0001) following Bayesian information criterion model selection in contrast to skeletal muscle index that remained prognostic for PFS (P = 0.009). Applying stricter criteria for transferability, MA represented the only prognostic body composition parameter for OS, selected in >80% of bootstrap replicates. Finally, Cox model‐derived survival curves indicated that large differences in MA translate into only moderate differences in expected OS in this cohort.
Conclusions
Among body composition parameters, only MA has robust prognostic impact for OS. Data suggest that treatment approaches targeting muscle quality are unlikely to prolong OS noticeably on their own in advanced gastric cancer patients, indicating that multimodal approaches should be pursued in the future.

Staging of nutrition disorders in non‐small‐cell lung cancer patients: utility of skeletal muscle mass assessment

27-08-2019 – Sami Antoun, Hugues Morel, Pierre‐Jean Souquet, Veerle Surmont, David Planchard, Franck Bonnetain, Pascal Foucher, Thomas Egenod, Ivan Krakowski, Hélène Gaudin, Didier Debieuvre

Journal Article

Abstract
Background
An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia skeletal muscle mass (SMM) loss, inflammation, and anorexia. The aim of this study was to stage CAX in non‐small‐cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters.
Methods
This was a cross‐sectional and non‐interventional multicentre study. SMM was assessed by analysing L3 computed tomography‐scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ‐C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ).
Results
Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0–1, and the tumour stage was mainly IIIB‐IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre‐CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K‐RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre‐CAX patients. Overall, 43.8% of pre‐CAX patients had only sarcopenia with limited weight loss (≤2%) and no anorexia.
Conclusions
This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX.

Impact of preoperative body compositions on survival following resection of biliary tract cancer

27-08-2019 – Seung Bae Yoon, Moon Hyung Choi, Meiying Song, Ju Hyun Lee, In Seok Lee, Myung Ah. Lee, Tae Ho Hong, Eun Sun Jung, Myung‐Gyu Choi

Journal Article

Abstract
Background
Although surgical resection is the only potentially curative treatment for biliary tract cancer, the prognosis remains poor after a major operation such as pancreatoduodenectomy or hepatectomy. We aimed to investigate the impact of preoperative body compositions on long‐term survival of patients undergoing resection of biliary tract cancer.
Methods
We analysed data of patients diagnosed with biliary tract cancer who underwent surgery from 2009 to 2015. Skeletal muscle area, skeletal muscle radiation attenuation, and visceral and subcutaneous adipose tissue areas were measured from the computed tomography images at L3 vertebral levels obtained before resection of cancer. Patients were divided into two groups based on the sex‐specific median values for each parameter, and long‐term survival was compared between the groups.
Results
A total of 371 patients (women, 39.6%; mean age, 66.2 ± 9.6 years) were finally included in the analysis. Patients with low skeletal muscle index (SMI) had significantly shorter median survival than those with high SMI (29 vs. 39 months; P = 0.026). Patients with low skeletal muscle attenuation (SMA) also showed reduced survival compared with those with high SMA (median survival 25 vs. 60 months; P = 0.002). Combining these two factors, survival was highest in the high SMI/high SMA group (reference) and lowest in the low SMI/low SMA group (hazard ratio, 2.18; 95% confidence interval, 1.44–3.30). Visceral and subcutaneous adipose tissue areas were not associated with long‐term survival.
Conclusions
Low SMI and low SMA on computed tomography scan have a negative impact on survival after resection of biliary tract cancer. They can be used in preoperative risk assessment to assist in treatment decision making.

Myosteatosis is associated with poor physical fitness in patients undergoing hepatopancreatobiliary surgery

27-08-2019 – Malcolm A. West, David P.J. Dijk, Fredrick Gleadowe, Thomas Reeves, John N. Primrose, Mohammed Abu Hilal, Mark R. Edwards, Sandy Jack, Sander S.S. Rensen, Michael P.W. Grocott, Denny Z.H. Levett, Steven W.M. Olde Damink

Journal Article

Abstract
Background
Body composition assessment, measured using single‐slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia (i.e. low skeletal muscle mass), myosteatosis i.e. low skeletal muscle radiation attenuation (SM‐RA), and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post‐operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery.
Methods
A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single‐slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold (O2 at AT), oxygen uptake at peak exercise (O2 peak), skeletal muscle mass, and SM‐RA.
Results
Of 123 patients recruited 77 men (63%), median age 66.9 ± 11.7, median body mass index 27.3 ± 5.2, 113 patients had good‐quality abdominal CT scans available and were included. Of the CT body composition variables, SM‐RA had the strongest correlation with O2 peak (r = 0.57, P < 0.001) and O2 at AT (r = 0.45, P < 0.001) while skeletal muscle mass was only weakly associated with O2 peak (r = 0.24, P < 0.010). In the multivariate analysis, only SM‐RA was associated with O2 peak (B = 0.25, 95% CI 0.15–0.34, P < 0.001, R2 = 0.42) and O2 at AT (B = 0.13, 95% CI 0.06–0.18, P < 0.001, R2 = 0.26).
Conclusions
There is a positive association between preoperative CT SM‐RA and preoperative physical fitness (O2 at AT and at peak). This study demonstrates that myosteatosis, and not sarcopenia, is associated with reduced aerobic physical fitness. Combining both myosteatosis and physical fitness variables may provide additive risk stratification accuracy and guide interventions during the perioperative period.

The role of SIRT1 in skeletal muscle function and repair of older mice

27-08-2019 – Matthew J. Myers, Danielle L. Shepherd, Andrya J. Durr, David S. Stanton, Junaith S. Mohamed, John M. Hollander, Stephen E. Alway

Journal Article

Abstract
Background
Sirtuin 1 (SIRT1) is a NAD+ sensitive deacetylase that has been linked to longevity and has been suggested to confer beneficial effects that counter aging‐associated deterioration. Muscle repair is dependent upon satellite cell function, which is reported to be reduced with aging; however, it is not known if this is linked to an aging‐suppression of SIRT1. This study tested the hypothesis that Sirtuin 1 (SIRT1) overexpression would increase the extent of muscle repair and muscle function in older mice.
Methods
We examined satellite cell dependent repair in tibialis anterior, gastrocnemius, and soleus muscles of 13 young wild‐type mice (20–30 weeks) and 49 older (80+ weeks) mice that were controls (n = 13), overexpressed SIRT1 in skeletal muscle (n = 14), and had a skeletal muscle SIRT1 knockout (n = 12) or a satellite cell SIRT1 knockout (n = 10). Acute muscle injury was induced by injection of cardiotoxin (CTX), and phosphate‐buffered saline was used as a vector control. Plantarflexor muscle force and fatigue were evaluated before or 21 days after CTX injection. Satellite cell proliferation and mitochondrial function were also evaluated in undamaged muscles.
Results
Maximal muscle force was significantly lower in control muscles of older satellite cell knockout SIRT1 mice compared to young adult wild‐type (YWT) mice (P < 0.001). Mean contraction force at 40 Hz stimulation was significantly greater after recovery from CTX injury in older mice that overexpressed muscle SIRT1 than age‐matched SIRT1 knockout mice (P < 0.05). SIRT1 muscle knockout models (P < 0.05) had greater levels of p53 (P < 0.05 MKO, P < 0.001 OE) in CTX‐damaged tissues as compared to YWT CTX mice. SIRT1 overexpression with co‐expression of p53 was associated with increased fatigue resistance and increased force potentiation during repeated contractions as compared to wild‐type or SIRT1 knockout models (P < 0.001). Muscle structure and mitochondrial function were not different between the groups, but proliferation of satellite cells was significantly greater in older mice with SIRT1 muscle knockout (P < 0.05), but not older SIRT1 satellite cell knockout models, in vitro, although this effect was attenuated in vivo after 21 days of recovery.
Conclusions
The data suggest skeletal muscle structure, function, and recovery after CTX‐induced injury are not significantly influenced by gain or loss of SIRT1 abundance alone in skeletal muscle; however, muscle function is impaired by ablation of SIRT1 in satellite cells. SIRT1 appears to interact with p53 to improve muscle fatigue resistance after repair from muscle injury.

Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation

27-08-2019 – Ashley J. Smuder, Aaron B. Morton, Stephanie E. Hall, Michael P. Wiggs, Bumsoo Ahn, Nicholas R. Wawrzyniak, Kurt J. Sollanek, Kisuk Min, Oh Sung Kwon, W. Bradley Nelson, Scott K. Powers

Journal Article

Abstract
Background
Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator‐induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity‐induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF‐κB and Fox
O transcriptional activity, which contribute to VIDD. In addition, exercise‐induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise‐induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD.
Methods
Cause and effect was determined by inhibiting the endurance exercise‐induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (r
AAV‐HSP72) or pharmacological (BGP‐15) overexpression is sufficient to prevent VIDD.
Results
Our results demonstrate that the exercise‐induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both r
AAV‐HSP72 and BGP‐15‐induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF‐κB and Fox
O target genes.
Conclusions
HSP72 overexpression in the diaphragm is an effective intervention to prevent MV‐induced oxidative stress and the transcriptional activity of NF‐κB and Fox
O. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD.

Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI

27-08-2019 – Douglas W. Gould, Emma L. Watson, Thomas J. Wilkinson, Joanne Wormleighton, Soteris Xenophontos, Joao L. Viana, Alice C. Smith

Journal Article

Abstract
Background
Chronic kidney disease (CKD) is a catabolic condition associated with muscle wasting and dysfunction, which associates with morbidity and mortality. There is a need for simple techniques capable of monitoring changes in muscle size with disease progression and in response to interventions aiming to increase muscle mass and function. Ultrasound is one such technique; however, it is unknown how well changes in muscle cross‐sectional area (CSA) measured using ultrasound relate to changes in whole muscle volume measured using magnetic resonance imaging. We tested whether rectus femoris CSA (RF‐CSA) could be used as a valid indication of changes in quadriceps muscle volume as a single measure of muscle size and following a 12 week exercise intervention that resulted in muscle hypertrophy.
Methods
Secondary analysis of data was collected from the Ex
Tra CKD study (ISRCTN 36489137). Quadriceps muscle size was assessed from 36 patients with non‐dialysis CKD before and after 12 weeks of supervised exercise that resulted in muscle hypertrophy.
Results
Strong positive correlations were observed between RF‐CSA and quadriceps volume at baseline (r2 = 0.815, CI 0.661 to 0.903; P < 0.001) and following 12 week exercise (r2 = 0.845, CI 0.700 to 0.923; P < 0.001). A moderate positive association was also observed between changes in RF‐CSA and quadriceps following exercise training (rho = 0.441, CI 0.085 to 0.697; P = 0.015). Bland–Altman analysis revealed a small bias (bias 0.6% ± 12.5) between the mean percentage changes in RF‐CSA and quadriceps volume but wide limits of agreement from −24 to 25.
Conclusions
Rectus femoris CSA appears to be a reliable index of total quadriceps volume as a simple measure of muscle size, both as a single observation and in response to exercise training in non‐dialysis CKD patients.

Muscle radiodensity loss during cancer therapy is predictive for poor survival in advanced endometrial cancer

27-08-2019 – Jie Lee, Jhen‐Bin Lin, Meng‐Hao Wu, Ya‐Ting Jan, Chih‐Long Chang, Chueh‐Yi Huang, Fang‐Ju Sun, Yu‐Jen Chen

Journal Article

Abstract
Background
Treatment‐related toxicities and decreased levels of patient performance during cancer therapy might contribute to body composition changes and thereby impact outcomes. However, the effect of longitudinal body composition changes on outcomes in patients with advanced endometrial cancer is unknown. This study investigated the association between body composition changes during staging surgery and adjuvant chemoradiotherapy and outcomes in patients with stage III endometrial cancer.
Methods
Pretreatment and post‐treatment computed tomography (CT) images of 131 patients with stage III endometrial cancer who were treated between 2008 and 2016 were analysed. All CT images were contrast enhanced and acquired according to the standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured from two sets of CT images obtained at the level of the third lumbar vertebra. The skeletal muscle gauge was calculated by multiplying SMI by SMD (SMI × SMD). Predictors of overall survival and progression‐free survival were identified using Cox regression models.
Results
The median follow‐up was 50.6 (range 12.1–117.0) months. Overall, body mass index (BMI) changes during treatment were 0.4% per 210 days (95% confidence interval: −0.6 to 1.4; P = 0.41), and patients experienced an average SMD loss of 2.1% per 210 days (95% confidence interval: −4.0 to −0.2; P = 0.03). Weight loss and SMD loss ≥5% were observed in 23 (17.6%) and 54 (41.2%) patients, respectively. The changes in SMD did not correlate with those in BMI (Spearmans ρ for SMD, −0.13; P = 0.13). SMD change (per 1 Hounsfield unit/210 days decrease) was independently associated with poorer overall survival (hazard ratio: 1.32, 95% confidence interval: 1.14–1.52; P < 0.001) and progression‐free survival (hazard ratio: 1.28, 95% confidence interval: 1.12–1.43; P < 0.001). Our results did not show association between survival and pretreatment myosteatosis and sarcopenia or changes in SMI and total adipose tissue index during treatment. The pretreatment skeletal muscle gauge was associated with treatment modifications such as delays, dose reductions, and discontinuation of chemotherapy.
Conclusions
Skeletal muscle radiodensity decreased significantly during treatment and was independently associated with poorer survival in patients with stage III endometrial cancer who underwent staging surgery and adjuvant chemoradiotherapy. SMD loss was occult and occurred independently of BMI change.

Psoas muscle fluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose uptake associated with the incidence of existing and incipient metabolic derangement

27-08-2019 – Ji Young Kim, Dae Won Jun, Jun Choi, Eunwoo Nam, Donghee Son, Yun Young Choi

Journal Article

Abstract
Background
Skeletal muscle glucose utilization is an important component of whole‐body glucose consumption in normal humans. Fluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) is a non‐invasive molecular imaging probe for evaluating tissue glucose utilization. It remains unclear whether or not 18F‐FDG uptake by skeletal muscle has utility as a biomarker for metabolic derangement. We investigated the utility of measurement of muscle 18F‐FDG positron emission tomography/computed tomography uptake as a surrogate marker for existing and incipient metabolic abnormalities.
Methods
Fluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) uptakes of insulin‐sensitive organs (liver, pancreas, mesenteric visceral fat, psoas muscle, and abdominal subcutaneous fat) and their association with metabolic abnormalities were evaluated in an experimental group comprising 91 men and 66 women (mean age 49.9 ± 11.1 years). In this cross‐sectional cohort, we assessed the predictive power of the optimal cut‐off 18F‐FDG uptake maximum standardized uptake value (SUVmax). We confirmed its feasibility and reliability for diagnosis of existing and incipient metabolic derangement in the validation group (longitudinal cohort comprising 91 men and 67 women; mean age 52.6 ± 7.9 years).
Results
Fluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) uptake (SUVmax) of psoas muscle was strongly correlated with clinical metabolic parameters in the experimental group. It was positively correlated with waist circumference, body mass index, fasting glucose, triglyceride, systolic and diastolic pressure, and negatively correlated with high‐density lipoprotein cholesterol levels (for all, P < 0.05). SUVmax of the psoas muscle also showed the best area under the curve value (0.779) as a predictor of metabolic syndrome (Met
S) in the experimental group. Using the optimal cut‐off SUVmax of 1.34, the sensitivity, specificity, accuracy, positive, and negative predictive value for predicting existing Met
S in the experimental group were 70.0%, 84.6%, 80.9%, 60.9%, and 89.2%, respectively. In the validation group, corresponding values were 47.6%, 92.3%, 86.1%, 50.0%, and 91.6%, respectively. Existing and incipient Met
S were significantly higher in subjects with high 18F‐FDG uptake by the psoas muscle (SUVmax > 1.34). Subjects with higher psoas muscle SUVmax had a 3.3‐fold increased risk of developing Met
S (P = 0.017).
Conclusions
Fluorine‐18‐labelled fluoro‐2‐deoxy‐d‐glucose (18F‐FDG) uptake of psoas muscle is a promising surrogate marker for existing and incipient metabolic derangement.

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

27-08-2019 – Yeonhee Hong, Jong Han Lee, Kwang Won Jeong, Cheol Soo Choi, Hee‐Sook Jun

Journal Article

Abstract
Background
Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved.
Methods
Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model.
Results
Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (Mu
RF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (Myo
G and Myo
D), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice.
Conclusions
GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis

27-08-2019 – Arthur Goron, Frédéric Lamarche, Sandrine Blanchet, Pascale Delangle, Uwe Schlattner, Eric Fontaine, Christophe Moinard

Journal Article

Abstract
Background
Animal studies and clinical data support the interest of citrulline as a promising therapeutic for sarcopenia. Citrulline is known to stimulate muscle protein synthesis, but how it affects energy metabolism to support the highly energy‐dependent protein synthesis machinery is poorly understood.
Methods
Here, we used myotubes derived from primary culture of mouse myoblasts to study the effect of citrulline on both energy metabolism and protein synthesis under different limiting conditions.
Results
When serum/amino acid deficiency or energy stress (mild uncoupling) were applied, citrulline stimulated muscle protein synthesis by +22% and +11%, respectively. Importantly, this increase was not associated with enhanced energy status (ATP/ADP ratio) or mitochondrial respiration. We further analysed the share of mitochondrial respiration and thus of generated ATP allocated to different metabolic pathways by using specific inhibitors. Our results indicate that addition of citrulline allocated an increased share of mitochondrially generated ATP to the protein synthesis machinery under conditions of both serum/amino acid deficiency (+28%) and energy stress (+21%). This reallocation was not because of reduced ATP supply to DNA synthesis or activities of sodium and calcium cycling ion pumps.
Conclusions
Under certain stress conditions, citrulline increases muscle protein synthesis by specifically reallocating mitochondrial fuel to the protein synthesis machinery. Because ATP/ADP ratios and thus Gibbs free energy of ATP hydrolysis remained globally constant, this reallocation may be linked to decreased activation energies of one or several ATP (and GTP)‐consuming reactions involved in muscle protein synthesis.

Skeletal muscle mass loss and dose‐limiting toxicities in metastatic colorectal cancer patients

27-08-2019 – Sophie Kurk, Petra Peeters, Rebecca Stellato, B. Dorresteijn, Pim Jong, Marion Jourdan, Geert‐Jan Creemers, Frans Erdkamp, Felix Jongh, Peter Kint, Lieke Simkens, Bea Tanis, Manuel Tjin‐A‐Ton, Ankie Van Der Velden, Cornelis Punt, Miriam Koopman, Anne May

Journal Article

Abstract
Background
Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first‐line maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose‐limiting toxicities (DLTs) during CAP‐B and CAPOX‐B.
Methods
Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs.
Results
One hundred eighty‐two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP‐B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX‐B. At the start of CAP‐B and CAPOX‐B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non‐sarcopenic at the start of CAP‐B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX‐B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2). Sarcopenia at the start of CAP‐B was not associated with DLTs relative risk 0.87 (95% confidence interval 0.64–1.19), whereas patients with >2% SMI loss had a significantly higher risk of DLTs 1.29 (1.01–1.66). At the start of subsequent CAPOX‐B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss 1.78 (1.06–3.01) or sarcopenia 1.75 (1.08–2.86). After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX‐B sarcopenia vs. non‐sarcopenic: 0.86 (0.69–1.08) and SMI loss vs. stable/gain: 0.83 (0.65–1.07). In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs.
Conclusions
In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

27-08-2019 – Savina Apolloni, Susanna Amadio, Paola Fabbrizio, Giovanna Morello, Antonio Gianmaria Spampinato, Emanuele Claudio Latagliata, Illari Salvatori, Daisy Proietti, Alberto Ferri, Luca Madaro, Stefano Puglisi‐Allegra, Sebastiano Cavallaro, Cinzia Volonté

Journal Article

Abstract
Background
Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti‐inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine‐mediated therapeutic strategy in ALS mice.
Methods
We adopted an integrative multi‐omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)‐G93A mice that recapitulate key ALS features, with the brain‐permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1‐G93A motor neuron‐like cells.
Results
We identified 13 histamine‐related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine‐related genes overlapped with genomic regions disrupted by DNA copy number and with ALS‐linked pathogenic variants. Histidine treatment in SOD1‐G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro.
Conclusions
Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine‐related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi‐gene network responsible for ALS and, furthermore, in the drug development process.

Effect of weight loss on the estimated glomerular filtration rates of obese patients at risk of chronic kidney disease: the RIGOR‐TMU study

27-08-2019 – Yen‐Chung Lin, Yi‐Jen Lai, Yi‐Chun Lin, Chiung‐Chi Peng, Kuan‐Chou Chen, Ming‐Tsang Chuang, Mai‐Szu Wu, Tzu‐Hao Chang

Journal Article

Abstract
Background
Weight‐reduction therapies, including bariatric surgery (BS), are standard treatments for severely obese patients with type 2 diabetes; however, the outcomes of these therapies are inconclusive for obese patients with chronic kidney disease (CKD). This study aimed to investigate the effects of BS or non‐surgical interventions on the estimated glomerular filtration rate (e
GFR) and to determine whether BS can be recommended for renal function preservation based on body mass index (BMI) and e
GFR changes in obese patients with CKD.
Methods
This study used data from the weight Reduction Intervention on GFR in Obese Patients with Renal Impairment‐Taipei Medical University (TMU) study, which was a large, long‐term, propensity score‐matched cohort study based on clinical data from patients who registered at weight‐reduction centres at TMU and its affiliated hospitals from 2008 to 2016. The patients were stratified according to whether they had undergone BS and into the mild, moderate, and high CKD risk groups using the Kidney Disease: Improving Global Outcomes guidelines. The primary outcome was the e
GFR calculated using the Taiwan Chronic Kidney Disease‐Epidemiology Collaboration equation. Cox regression models were used to determine hazard ratios (HRs) for e
GFR decreases ≥25%.
Results
A total of 4332 obese patients were enrolled in this study. After propensity score matching, 1620 patients, including 60.2% women, with a mean age of 36.5 (9.9) years were divided into BS or non‐surgery groups (n = 810 per group). The overall mean e
GFRs increased by 4.4 (14) m
L/min·1.73 m2 and decreased by 6.4 (16.0) m
L/min·1.73 m2 in the BS and non‐surgery groups, respectively. The decrease in BMI in the BS and non‐surgery groups were 2.5 and 1.3 kg/m2, respectively. In the moderate/high CKD risk BS group, a significant correlation was evident between an increased e
GFR and a reduced BMI (Spearmans correlation −0.229, P < 0.001). The Cox regression analysis showed that the BS group had a significantly lower risk of an e
GFR decline ≥25% at 12 months adjusted HR (a
HR) 0.47, P = 0.03). After BS, obese patients with hypertension or albuminuria had significantly lower risks of e
GFR declines ≥25% (a
HR 0.37, P = 0.02 and a
HR 0.13, P = 0.0018, respectively).
Conclusions
Bariatric surgery was associated with e
GFR preservation in all obese patients and, particularly, in those with moderate‐to‐high CKD risks. A longer term outcome study is warranted to determine the benefits of BS for CKD patients.

Cancer‐driven changes link T cell frequency to muscle strength in people with cancer: a pilot study

27-08-2019 – Aditi Narsale, Rosa Moya, Jasmin Ma, Lindsey J. Anderson, Daniel Wu, Jose M. Garcia, Joanna D. Davies

Journal Article

Abstract
Background
Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4+ precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti‐cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer.
Methods
The frequency of circulating CD4+ and CD8+ naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real‐time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one‐repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual‐energy X‐ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses.
Results
Our data show significant correlations between (i) higher frequencies of CD8+ naïve (P = 0.02) and effector memory (P = 0.003) T cells and lower frequencies of CD8+ central memory T cells (P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index (P = 0.04), (iii) lower frequency of CD8+ T cells that express CD95 with greater stair climb power (P = 0.003), (iv) higher frequency of T cells that co‐express CD197 and CD45RA and greater one‐repetition maximum knee extension strength (P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment (P = 0.004) in people with cancer.
Conclusions
We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow‐up study with a larger cohort to test the validity of the findings.

Chemotherapy‐induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol

27-08-2019 – Daniel I. Brierley, Joe R. Harman, Natasha Giallourou, Emma Leishman, Anna Emily Roashan, Ben A.D. Mellows, Heather B. Bradshaw, Jonathan R. Swann, Ketan Patel, Benjamin J. Whalley, Claire M. Williams

Journal Article

Abstract
Background
Muscle wasting, anorexia, and metabolic dysregulation are common side‐effects of cytotoxic chemotherapy, having a dose‐limiting effect on treatment efficacy, and compromising quality of life and mortality. Extracts of Cannabis sativa, and analogues of the major phytocannabinoid Δ9‐tetrahydrocannabinol, have been used to ameliorate chemotherapy‐induced appetite loss and nausea for decades. However, psychoactive side‐effects limit their clinical utility, and they have little efficacy against weight loss. We recently established that the non‐psychoactive phytocannabinoid cannabigerol (CBG) stimulates appetite in healthy rats, without neuromotor side‐effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad‐spectrum chemotherapy agent cisplatin.
Methods
An acute cachectic phenotype was induced in adult male Lister‐hooded rats by 6 mg/kg (i.p.) cisplatin. In total 66 rats were randomly allocated to groups receiving vehicle only, cisplatin only, or cisplatin and 60 or 120 mg/kg CBG (po, b.i.d.). Feeding behavior, bodyweight and locomotor activity were recorded for 72 hours, at which point rats were sacrificed for post‐mortem analyses. Myofibre atrophy, protein synthesis and autophagy dysregulation were assessed in skeletal muscle, plasma metabolic profiles were obtained by untargeted 1H‐NMR metabonomics, and levels of endocannabinoid‐like lipoamines quantified in plasma and hypothalami by targeted HPLC‐MS/MS lipidomics.
Results
CBG (120 mg/kg) modestly increased food intake, predominantly at 36‐60hrs (p<0.05), and robustly attenuated cisplatin‐induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin‐induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6‐mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide‐ranging aberrant metabolic phenotype (Q2Ŷ=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Ŷ=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin‐induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N‐acyl glycine concentrations which were negatively associated with the anti‐cachectic effects of CBG treatment.
Conclusions
Endocannabinoid‐like lipoamines may have hitherto unrecognized roles in the metabolic side‐effects associated with chemotherapy, with the N‐acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG‐based treatments may represent a novel therapeutic option for chemotherapy‐induced cachexia, warranting investigation in tumour‐bearing cachexia models.

Muscle wasting and function after muscle activation and early protocol‐based physiotherapy: an explorative trial

27-08-2019 – Tobias Wollersheim, Julius J. Grunow, Niklas M. Carbon, Kurt Haas, Johannes Malleike, Sara F. Ramme, Joanna Schneider, Claudia D. Spies, Sven Märdian, Knut Mai, Simone Spuler, Jens Fielitz, Steffen Weber‐Carstens

Journal Article

Abstract
Background
Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)‐cohort. We aimed to investigate clinical and molecular benefits or detriments of early mobilization and muscle activating measures in a high‐risk ICU‐acquired weakness cohort.
Methods
Fifty patients with a SOFA score ≥9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole‐body vibration in addition to early protocol‐based physiotherapy (intervention) or early protocol‐based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow‐up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol‐based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU‐acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier.
Results
ICU‐acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median IQR: CPP 3.3 3.0–4.3; control 3.0 2.7–3.4; intervention 3.0 2.1–3.8; P > 0.05 for all), ICU discharge (MRC median IQR: CPP 3.8 3.4–4.4; control 3.9 3.3–4.0; intervention 3.6 2.8–4.0; P > 0.05 for all), and 12 month follow‐up (MRC median IQR: control 5.0 4.3–5.0; intervention 4.8 4.3–5.0; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross‐sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up‐regulated gene expression for myosin heavy chains (fold change median IQR: MYH1 2.3 1.1–2.7; MYH2 0.7 0.2–1.8; MYH4 5.1 2.2–15.3) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32.
Conclusions
In our patients with sepsis syndrome at high risk for ICU‐acquired weakness muscle activating measures in addition to early protocol‐based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow‐up. Yet it prevented muscle atrophy.

Effectiveness of a multimodal intervention in functionally impaired older people with type 2 diabetes mellitus

27-08-2019 – Leocadio Rodriguez‐Mañas, Olga Laosa, Bruno Vellas, Giuseppe Paolisso, Eva Topinkova, Juan Oliva‐Moreno, Isabelle Bourdel‐Marchasson, Mikel Izquierdo, Kerry Hood, Andrej Zeyfang, Giovanni Gambassi, Mirko Petrovic, Tim C. Hardman, Mark J. Kelson, Ivan Bautmans, Gabor Abellan, Michelangela Barbieri, Luz M. Peña‐Longobardo, Sophie C. Regueme, Riccardo Calvani, Stefanie De Buyser, Alan J. Sinclair, on behalf of the European MID‐Frail Consortium

Journal Article

Abstract
Background
Type 2 diabetes, a highly prevalent chronic disease, is associated with increasing frailty and functional decline in older people. We aimed to evaluate the effectiveness of a multimodal intervention on functional performance in frail and pre‐frail participants aged ≥70 years with type 2 diabetes mellitus.
Methods
The MID‐Frail study was a cluster‐randomized multicenter clinical trial conducted in 74 trial sites across seven European countries. The trial recruited 964 participants who were aged >70 years mean age in intervention group, 78.4 (SD 5.6) years, 49.2% male and 77.6 (SD 5.29) years, 52.4% male in usual care group, with type diabetes mellitus and determined to be frail or pre‐frail using Frieds frailty phenotype. Participants were allocated by trial site to follow either usual care (UCG) or intervention procedures (IG). Intervention group participants received a multimodal intervention composed of (i) an individualized and progressive resistance exercise programme for 16 weeks; (ii) a structured diabetes and nutritional educational programme over seven sessions; and (iii) Investigator‐linked training to ensure optimal diabetes care. Short Physical Performance Battery (SPPB) scores were used to assess change in functional performance at 12 months between the groups. An analysis of the cost‐effectiveness of the intervention was undertaken using the incremental cost‐effectiveness ratio (ICER). Secondary outcomes included mortality, hospitalization, institutionalization, quality of life, burden on caregivers, the frequency and severity of hypoglycaemia episodes, and the cost‐effectiveness of the intervention.
Results
After 12 months, IG participants had mean SPPB scores 0.85 points higher than those in the UCG (95% CI, 0.44 to 1.26, P < 0.0001). Dropouts were higher in frail participants and in the intervention group, but significant differences in SPPB between treatment groups remained consistent after sensitivity analysis. Estimates suggest a mean saving following intervention of 428.02 EUR (2016) per patient per year, with ICER analysis indicating a consistent benefit of the described health care intervention over usual care. No statistically significant differences between groups were detected in any of the other secondary outcomes.
Conclusions
We have demonstrated that a 12 month structured multimodal intervention programme across several clinical settings in different European countries leads to a clinically relevant and cost‐effective improvement in the functional status of older frail and pre‐frail participants with type 2 diabetes mellitus.

The Journal of Cachexia, Sarcopenia and Muscle in 2019

27-08-2019 – Stephan Haehling, Nicole Ebner, Stefan D. Anker

Editorial

Issue Information

27-08-2019 –

No abstract is available for this article.

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

23-08-2019 – Alexander Hahn, Melanie Kny, Cristina Pablo‐Tortola, Mihail Todiras, Michael Willenbrock, Sibylle Schmidt, Katrin Schmoeckel, Ilka Jorde, Marcel Nowak, Ernst Jarosch, Thomas Sommer, Barbara M. Bröker, Stephan B. Felix, Claus Scheidereit, Steffen Weber‐Carstens, Christian Butter, Friedrich C. Luft, Jens Fielitz

Journal Article

Abstract
Background
Critically ill patients frequently develop muscle atrophy and weakness in the intensive‐care‐unit setting intensive care unit‐acquired weakness (ICUAW). Sepsis, systemic inflammation, and acute‐phase response are major risk factors. We reported earlier that the acute‐phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation‐induced muscle atrophy.
Methods
We performed cell‐based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol‐Myers Squibb (BMS)‐345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation‐induced muscle atrophy and the effects of BMS‐345541 treatment.
Results
The SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll‐like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor ‘kappa‐light‐chain‐enhancer’ of activated B‐cells (NF‐κB) p65 via TLR2 and TLR4 leading to an increased binding of NF‐κB to NF‐κB response elements in the promoter region of its target genes resulting in an increased expression of NF‐κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF‐κB signalling by BMS‐345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS‐345541 diminished inflammation‐induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: −21.2% and BMS‐345541: −10.4%; P < 0.05), tibialis anterior (vehicle: −22.7% and BMS‐345541: −17.1%; P < 0.05) and soleus (vehicle: −21.1% and BMS‐345541: −11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross‐sectional area showed that BMS‐345541 reduced inflammation‐induced atrophy of slow/type I and fast/type II myofibers compared with vehicle‐treated septic mice. BMS‐345541 reversed the inflammation‐induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/Mu
RF1, Fbxo32/Atrogin1, and Fbxo30/Mu
SA1.
Conclusions
SAA1 activates the TLR2/TLR4//NF‐κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF‐κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF‐κB p65 atrophy pathway could have utility in combatting ICUAW.

Metastasis and cachexia: alongside in clinics, but not so in animal models

22-08-2019 – Rebeka Tomasin, Ana Carolina Baptista Moreno Martin, Márcia Regina Cominetti

Journal Article, Review

Abstract
Cancer cachexia is a paraneoplastic syndrome characterized by lean mass wasting (with or without fat mass decrease), culminating in involuntary weight loss, which is the key clinical observation nowadays. There is a notable lack of studies involving animal models to mimic the clinical reality, which are mostly patients with cachexia and metastatic disease. This mismatch between the clinical reality and animal models could at least partly contribute to the poor translation observed in the field. In this paper, we retrieved and compared animal models used for cachexia research from 2017 and 10 years earlier (2007) and observed that very little has changed. Especially, clinically relevant models where cachexia is studied in an orthotopic or metastatic context were and still are very scarce. Finally, we described and supported the biological rationale behind why, despite technical challenges, these two phenomena—metastasis and cachexia—should be modelled in parallel, highlighting the overlapping pathways between them. To sum up, this review aims to contribute to rethinking and possibly switching the models currently used for cachexia research, to hopefully obtain better and more translational outcomes.

Predictivity of bioimpedance phase angle for incident disability in older adults

22-08-2019 – Kazuki Uemura, Takehiko Doi, Kota Tsutsumimoto, Sho Nakakubo, Min‐Ji Kim, Satoshi Kurita, Hideaki Ishii, Hiroyuki Shimada

Journal Article

Abstract
Background
Bioelectrical impedance analysis (BIA)‐derived phase angle is expected to be an efficient prognostic marker of health adverse events with aging as an alternative of muscle mass. We aimed to examine the predictive ability of phase angle for incident disability in community‐dwelling elderly and determine the optimal cut‐off values.
Methods
Community‐dwelling elderly aged ≥65 years (n = 4452; mean age = 71.8 ± 5.3 years, 48.3% women) without disability at baseline participated in this prospective cohort study. Phase angle and appendicular skeletal muscle mass (ASM) were examined using a multi‐frequency BIA at baseline. Other potential confounding factors (demographics, cognitive function, depressive symptoms, medications, and physical performance) were also assessed. Incident disability was monitored on the basis of long‐term care insurance certification.
Results
Over a follow‐up of 24 months, 4.0% (n = 174) experienced disability, with an overall incidence rate of 20.6 per 1000 person‐years. The Cox hazard regression analysis showed that phase angle, as a continuous variable, was independently associated with incident disability after adjusting the covariates male: hazard ratios (HRs) = 0.61, 95% confidence interval (CI) = 0.37–0.98; female: HR = 0.58, 95% CI = 0.37–0.90, although body mass index adjusted ASM was not. Receiver operating characteristic analysis indicated moderate predictive abilities of phase angle for incident disability male: area under the receiver operating characteristic curve (AUC) = 0.76, 95% CI = 0.70–0.83; female: AUC = 0.71, 95% CI = 0.65–0.76, while those of body mass index adjusted ASM were low (male: AUC = 0.59, 95% CI = 0.521–0.66; female: AUC = 0.58, 95% CI = 0.52–0.63). Multivariate Cox regression analysis showed that low phase angle categorized by cut‐off value (male, ≤4.95°; female, ≤4.35°) was independently related to increased risk of incident disability (HR = 1.95, 95% CI = 1.37–2.78).
Conclusions
Lower phase angle independently predicts the incident disability separately from known risk factors. BIA‐derived phase angle can be used as a valuable and simple prognostic tool to identify the elderly at risk of disability as targets of preventive treatment.

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

21-08-2019 – Kristine Pettersen, Sonja Andersen, Anna Veen, Unni Nonstad, Shinji Hatakeyama, Christian Lambert, Estelle Lach‐Trifilieff, Siver Moestue, Jana Kim, Bjørn Henning Grønberg, Alain Schilb, Carsten Jacobi, Geir Bjørkøy

Journal Article

Abstract
Background
The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development.
Methods
We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice.
Results
We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on m
RNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/m
L, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005).
Conclusions
Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

Defining barriers to implementation of nutritional advice in patients with cachexia

21-08-2019 – Rima Nasrah, Christina Van Der Borch, Mary Kanbalian, R. Thomas Jagoe

Journal Article

Abstract
Background
Cancer cachexia is a multidimensional wasting syndrome and a reduced dietary intake is both common and strongly correlated with degree of weight loss. Many patients with cachexia do not achieve recommended dietary intake even after nutritional counselling. Prior reports suggest this is likely due to barrier symptoms, but other potential contributory factors have not been studied in detail.
Methods
Dietitian‐assigned barriers to successful nutritional intervention were recorded at each visit in all patients attending a multidisciplinary clinic for management of cancer cachexia. The barriers were grouped into 15 categories and classified as either symptom‐related or not symptom‐related. In addition, symptom scores, dietary intake, and weight change were recorded.
Results
Data on 94 new patients showed that 89% of patients had at least one major barrier. Four of the five most common barriers and 65% of all barriers identified were not symptom‐related. Over sequential visits the specific barrier(s) in any one patient changed approximately 50% of the time. However, the presence of barriers did not render patients refractory to nutritional intervention and with intervention from the CNR‐JGH team, mean dietary intake increased significantly.
Conclusions
In advanced cancer patients with cachexia, non‐symptom‐related barriers to nutritional intervention are more common than symptom‐related. Barriers are dynamic, and repeated careful evaluation over time is required to achieve optimal impact with nutritional intervention in cancer cachexia. Members of the multidisciplinary team need appropriate expertise to address the barriers identified and achieve optimal results with nutritional intervention.

Associations of fat‐soluble micronutrients and redox biomarkers with frailty status in the FRAILOMIC initiative

21-08-2019 – Bastian Kochlik, Wolfgang Stuetz, Karine Pérès, Sophie Pilleron, Catherine Féart, Francisco José García García, Stefania Bandinelli, David Gomez‐Cabrero, Leocadio Rodriguez‐Mañas, Tilman Grune, Daniela Weber

Journal Article

Abstract
Background
A poor fat‐soluble micronutrient (FMN) and a high oxidative stress status are associated with frailty. Our aim was to determine the cross‐sectional association of FMNs and oxidative stress biomarkers protein carbonyls (Pr
Carb) and 3‐nitrotyrosine with the frailty status in participants older than 65 years.
Methods
Plasma levels of vitamins A (retinol), D3, E (α‐tocopherol and γ‐tocopherol) and carotenoids (α‐carotene and β‐carotene, lycopene, lutein/zeaxanthin, and β‐cryptoxanthin), Pr
Carb, and 3‐nitrotyrosine were measured in 1450 individuals of the FRAILOMIC initiative. Participants were classified into robust, pre‐frail, and frail using Frieds frailty criteria. Associations between biomarkers and frailty status were assessed by general linear and logistic regression models, both adjusted for cohort, season of blood sampling, gender, age, height, weight, and smoking.
Results
Robust participants had significantly higher vitamin D3 and lutein/zeaxanthin concentrations than pre‐frail and frail subjects; had significantly higher γ‐tocopherol, α‐carotene, β‐carotene, lycopene, and β‐cryptoxanthin concentrations than frail subjects, and had significantly lower Pr
Carb concentrations than frail participants in multivariate linear models. Frail subjects were more likely to be in the lowest than in the highest tertile for vitamin D3 (adjusted odds ratio: 2.15; 95% confidence interval: 1.42–3.26), α‐tocopherol (2.12; 1.39–3.24), α‐carotene (1.69; 1.00–2.88), β‐carotene (1.84; 1.13–2.99), lycopene (1.94; 1.24–3.05), lutein/zeaxanthin (3.60; 2.34–5.53), and β‐cryptoxanthin (3.02; 1.95–4.69) and were more likely to be in the highest than in the lowest tertile for Pr
Carb (2.86; 1.82–4.49) than robust subjects in multivariate regression models.
Conclusions
Our study indicates that both low FMN and high Pr
Carb concentrations are associated with pre‐frailty and frailty.

Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure

20-08-2019 – Jack O. Garnham, Lee D. Roberts, Talia Caspi, Moza M. Al‐Owais, Max Bullock, Peter P. Swoboda, Aaron Koshy, John Gierula, Maria F. Paton, Richard M. Cubbon, Mark T. Kearney, T. Scott Bowen, Klaus K. Witte

Journal Article

Abstract
Background
Previous studies in heart failure with reduced ejection fraction (HFr
EF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFr
EF.
Methods
Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age‐matched male (n = 45) and female (n = 11) patients with HFr
EF and healthy‐matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity.
Results
Compared with sex‐matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFr
EF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFr
EF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator‐activated receptor γ coactivator‐1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFr
EF patients.
Conclusions
These data provide novel evidence that HFr
EF induces divergent sex‐specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial ‘quantity’ in female patients and mitochondrial ‘quality’ in male patients. Therapeutic strategies to improve exercise tolerance in HFr
EF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.

Remarks on the design and analyses of longitudinal studies for cancer patients with anorexia and weight loss

20-08-2019 – Jennifer G. Le‐Rademacher, Elizabeth M. Storrick, Aminah Jatoi

Journal Article, Review

Abstract
Longitudinal data serve an important role in understanding the cancer anorexia weight loss syndrome and in testing interventions to palliative and treat patients who develop this syndrome. The element of time and the interrelatedness of data points define longitudinal data and add to the richness of this type of data. However, longitudinal data can also give rise to non‐random, missing data that can lead to flawed conclusions. This paper discusses these issues and suggests practical considerations for design and analysis of longitudinal cancer anorexia weight loss studies.

The Copenhagen Sarcopenia Study: lean mass, strength, power, and physical function in a Danish cohort aged 20–93 years

16-08-2019 – Charlotte Suetta, Bryan Haddock, Julian Alcazar, Tim Noerst, Ole M. Hansen, Helle Ludvig, Rikke Stefan Kamper, Peter Schnohr, Eva Prescott, Lars L. Andersen, Ulrik Frandsen, Per Aagaard, Jens Bülow, Peter Hovind, Lene Simonsen

Journal Article

Abstract
Background
Despite no international consensus on the diagnostic criteria for sarcopenia, low lean mass, muscle strength, and physical function are important risk factors for disability, frailty, and mortality in older individuals, as well as in a wide range of patients with muscle loss. Here, we provide a population‐based reference material of total and regional lean body mass, muscle strength/power parameters, and physical function in a healthy cohort of Danish men and women across the lifespan.
Methods
Volunteers aged 20–93 years from the Copenhagen City Heart Study were invited to establish a Danish reference material (Copenhagen Sarcopenia Study) on lean mass characteristics appendicular lean mass (ALM), i
DXA, GE Lunar, muscle function handgrip strength (HGS), Jamar dynamometer and leg extension power (LEP), Nottingham Power Rig, and physical function 30 s sit‐to‐stand test (STS), 10‐m maximal and habitual gait speed (GS).
Results
A total of 1305 participants 729 women (age: 56.4 ± 18.9 years, height: 1.66 ± 0.01 m, body mass index: 24.6 ± 4.3 kg/m2 and 576 men, age: 57.0 ± 17.5 years, height: 1.80 ± 0.07 m, body mass index: 26.0 ± 3.9 kg/m2 completed all measurements and were included in the present analysis. Lean mass characteristics (TLM, ALM, and ALM/h2) decreased with increasing age in both men and women (P < 0.001). Men demonstrated larger absolute and relative total ALM and higher HGS and LEP compared with women at all age intervals (P < 0.001). HGS and LEP decreased progressively with age in both men and women (P < 0.01); 30 s STS performance, habitual GS, and maximal GS decreased at an accellerated rate of decline with increasing age in both men and women (P < 0.001). Habitual GS was reduced in men and women aged ≥70 years, while maximal GS was reduced from the age of ≥60 years compared with young adults (P < 0.001). Regardless of sex, 30 s STS was reduced from the age of ≥50 years compared with the young reference group (P < 0.001)Conclusions
While the power‐based measurements (LEP and 30 s STS) started to decline already at age +50 years, less power‐based parameters (GS and HGS) and lean mass characteristics (TLM, ALM, and ALM/h2) remained unaltered until after the age of +70 years. Notably, the cut‐off thresholds derived in the present study differed from earlier reference data, which underlines the importance of obtaining updated and local reference materials.

Prevalence, incidence, and clinical impact of cognitive–motoric risk syndrome in Europe, USA, and Japan: facts and numbers update 2019

13-08-2019 – Marcello Maggio, Fulvio Lauretani

Editorial

Abstract
A new syndrome called the ‘motoric–cognitive risk’ (MCR) syndrome has recently been proposed in older persons. According to this definition, the parallel impairment in muscle and brain function is more predictive for identifying subjects at risk of dementia than impairment a in single system alone. Epidemiological studies suggest that among older persons, enrolled in worldwide population‐based studies, 10% are affected by this syndrome, which confers a higher risk of future disability. In detail, the prevalence of MCR in Europe is around 8.0%, 7.0% in the United States, and 6.3% in Japan. The incidence of the MCR syndrome is estimated to be 65.2 per 1000 person years in adults aged 60 years or older. Many studies reported negative outcomes of the syndrome in older persons, emphasizing its clinical impact. In particular, in almost all longitudinal studies, MCR produces a three‐time increased risk of future dementia. In Europe, data from the In
CHIANTI study report an increased risk of 2.74 1.54–4.86, which is 2.49 1.52–4.10 in the United States and 3.27 1.55–6.90 in Japan. The studies in different continents are also consistent in showing an increased risk of all‐cause mortality, which is 1.50–1.87 in the Europeans and 1.69 1.08–2.02 for incident disability in Japan. For the identification of the MCR syndrome, different tests and procedures have been proposed, with a final ‘core‐battery’ that includes gait speed, dual‐task gait speed, the Montreal Cognitive Assessment and Trail Making Test A and B. The criteria used to select this core‐battery were based on the best accuracy for identifying older persons at risk of negative outcomes such as dementia, falls, aging‐related disabilities, and sensitivity to interventions. The selection of these tests will allow to start studies aimed to better capture older persons at higher risk of mobility and cognitive disability. By these tests, it will be possible to better evaluate the effect of treatment composing of tailored physical exercise, nutritional suggestions, and medical therapy to overturn negative effect of both cognitive and motoric frailty. This article provides an overview of the current knowledge of the MCR syndrome.

Inter‐individual variability in response to exercise intervention or usual care in hospitalized older adults

13-08-2019 – Mikel L. Sáez de Asteasu, Nicolás Martínez‐Velilla, Fabricio Zambom‐Ferraresi, Álvaro Casas‐Herrero, Eduardo L. Cadore, Robinson Ramirez‐Velez, Mikel Izquierdo

Journal Article

Abstract
Background
Exercise protocols applied during hospitalization can prevent functional and cognitive decline in older adults. The purpose of this study was to examine the individual response of acutely hospitalized patients to usual care and to physical exercise on functional capacity, muscle strength, and cognitive function and to assess the relationship with mortality at 1 year post‐discharge.
Methods
In a single‐blind randomized clinical trial, 370 hospitalized patients 56.5% women; mean age (standard deviation) 87.3 (4.9) years were allocated to an exercise intervention group (IG, n = 185) or a control group (CG, n = 185). The participants were older adults aged 75 years or older in an acute care unit in a tertiary public hospital in Navarra, Spain. The usual care group received habitual hospital care, which included physical rehabilitation when needed. The in‐hospital intervention included individualized multicomponent exercise training programme performed during 5–7 consecutive days (two sessions/day). Functional capacity was assessed with the Short Physical Performance Battery (SPPB) test and the Gait Velocity Test (GVT). Handgrip strength and cognitive function were also measured at admission and discharge. Patients in both groups were categorized as responders (Rs), non‐responders (NRs), and adverse responders (ARs) based on the individual response to each treatment during hospitalization.
Results
The prevalence of Rs was higher and the prevalence of NRs and ARs was lower in the intervention group than in the control group for functional capacity (SPPB IG: Rs 85.3%, NRs 8.7%, ARs 6.0% vs. CG: Rs 37.9%, NRs 28.8%, ARs 33.3% and GVT IG: Rs 51.2%, NRs 47.3, ARs 1.6% vs. CG: Rs 18.0%, NRs 67.7%, ARs 14.3%), muscle strength (IG: Rs 62.3%, NRs 26.5%, ARs 11.3% vs. CG: Rs 20.0%, NRs 38.0%, ARs 42.0%), and cognition (IG: Rs 41.5%, NRs 57.1%, ARs 1.4% vs. CG: Rs 13.8%, NRs 76.6%, ARs 9.7%) (all P < 0.001). The ARs for the GVT in the control group and the ARs for the SPPB in the intervention group had a significantly higher rate of mortality than the NRs and Rs in the equivalent groups (0.01 and 0.03, respectively) at follow‐up.
Conclusions
Older patients performing an individualized exercise intervention presented higher prevalence of Rs and a lower prevalence of NRs and ARs for functional capacity, muscle strength, and cognitive function than those who were treated with usual care during acute hospitalization. An adverse response on functional capacity in older patients to physical exercise or usual care during hospitalization was associated with mortality at 1 year post‐discharge.

Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle

11-08-2019 – Xiuqing Han, Lisbeth Liliendal Valbjørn Møller, Estelle De Groote, Kirstine Nyvold Bojsen‐Møller, Jonathan Davey, Carlos Henríquez‐Olguin, Zhencheng Li, Jonas Roland Knudsen, Thomas Elbenhardt Jensen, Sten Madsbad, Paul Gregorevic, Erik Arne Richter, Lykke Sylow

Journal Article

Abstract
Background
Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF‐β) superfamily, including activin A, which causes atrophy. TGF‐β superfamily ligands also negatively regulate insulin‐sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.
Methods
To elucidate if TGF‐β superfamily ligands regulate insulin action, we used an adeno‐associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet‐induced obese mice. We determined basal and insulin‐stimulated 2‐deoxy‐glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux‐en‐Y gastric bypass (RYGB).
Results
Fst288 muscle overexpression markedly increased in vivo insulin‐stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase‐E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin‐stimulated protein synthesis, but no correlation was observed between the Fst288‐driven hypertrophy and the increase in insulin‐stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin‐resistant diet‐induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (−24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.
Conclusions
We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase‐E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post‐RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF‐β superfamily ligands to improve insulin action and Fsts relevance to muscle wasting‐associated insulin‐resistant conditions in mice and humans.

Weight loss in heart failure is associated with increased mortality only in non‐obese patients without diabetes

09-08-2019 – Jacek T. Niedziela, Bartosz Hudzik, Krzysztof Strojek, Lech Poloński, Mariusz Gąsior, Piotr Rozentryt

Journal Article

Abstract
Background
Weight loss (WL) is an independent predictor of mortality in patients with heart failure (HF). Moderate WL is recommended for overweight or obese patients with type 2 diabetes mellitus (DM). The aim of this study was to assess the prognostic impact of body weight reduction on survival in patients with both HF with reduced ejection fraction (HFr
EF) and DM.
Methods
The study comprised patients with HFr
EF at the outpatient clinic. WL was defined as a body weight reduction of at least 7.5% during at least 6 months. Clinical features and 1 year mortality were analysed in WL and DM groups. Multivariate regression model was chosen to assess the predictive role of WL in HF patients with and without DM. The analysis regarding obesity before HF was also performed.
Results
The study comprised 777 patients with HFr
EF. Mean age was 53.2 ± 9.2, 12.0% were women, mean EF was 23.7 ± 6.0 %, and New York Heart Association III or IV class, DM, and WL were found in 60.5%, 33.3%, and 47.1% patients, respectively. WL was more prevalent in diabetic patients, comparing with those without DM (53.7% vs. 43.8%, respectively, 0.01), and was associated with higher 1 year mortality only in non‐diabetic group (17.6% for WL vs. 8.2% for non‐WL, log‐rank 0.001). In the multivariate analysis, WL was associated with a higher risk of 1 year mortality in non‐diabetic patients: HR 1.76 (1.05–2.95), 0.03 and only in the subgroup without obesity: HR 2.35 (1.28–4.32), 0.006. In non‐diabetic patients with obesity and in diabetic patients regardless of weight status, WL was not associated with worse prognosis (thereof, WL was excluded from the multivariate models).
Conclusions
Overall, WL in HFr
EF has emerged as a predictor of unfavourable outcomes only in non‐obese patients without DM. More importantly, this study has identified that the presence of DM (irrespective of weight status) or the presence of obesity in non‐diabetic patients abolished the unfavourable impact of WL on long‐term outcomes.

Sarcopenia and ovarian cancer survival: a systematic review and meta‐analysis

07-08-2019 – Jorne Ubachs, Janine Ziemons, Iris J.G. Minis‐Rutten, Roy F.P.M. Kruitwagen, Jos Kleijnen, Sandrina Lambrechts, Steven W.M. Olde Damink, Sander S. Rensen, Toon Van Gorp

Journal Article, Review

Abstract
Background
Sarcopenia is the loss of skeletal muscle mass and function that occurs with advancing age and certain diseases. It is thought to have a negative impact on survival in cancer patients. Routine computed tomography imaging is often used to quantify skeletal muscle in cancer patients. Sarcopenia is defined by a low skeletal muscle index (SMI). Skeletal muscle radiation attenuation (SMRA) is used to define muscle quality. The primary aim of this meta‐analysis was to study the association between sarcopenia or SMRA and overall survival (OS) or complications in patients with ovarian cancer.
Methods
Medline, Embase, CINAHL, and PEDro databases were searched from inception to 15 February 2019. Studies evaluating the prognostic effect of SMI and SMRA on ovarian cancer survival or surgical complications were included. Risk of bias and study quality were evaluated with the Quality in Prognosis Studies Instrument (QUIPS) according to the modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.
Results
The search strategy yielded 4262 hits in all four databases combined. Ten and eight studies were included for qualitative and quantitative analysis, respectively. Meta‐analysis revealed a significant association between the SMI and OS 0.007; hazard ratio (HR): 1.11, 95% confidence interval (CI): 1.03–1.20. SMRA was also significantly associated with OS (P < 0.001; HR: 1.14, 95% CI: 1.08–1.20). Association between the SMI and surgical complications had borderline statistical significance (0.05; HR: 1.23, 95% CI: 1.00–1.52). The risk of bias assessed with QUIPS was high in all studies. The quality of the evidence was very low.
Conclusions
Whereas our meta‐analysis indicated that a low SMI and low SMRA are associated with survival in ovarian cancer patients, the low quality of the source data precludes drawing definitive conclusions.

Associations between severe co‐morbidity and muscle measures in advanced non‐small cell lung cancer patients

06-08-2019 – Bjørn H. Grønberg, Christine Damgaard Valan, Tarje Halvorsen, Bjørg Sjøblom, Marit S. Jordhøy

Journal Article

Abstract
Background
Studies show that low skeletal muscle index (SMI) and low skeletal muscle density (SMD) are negative prognostic factors and associated with more toxicity from systemic therapy in cancer patients. However, muscle depletion can be caused by a range of diseases, and many cancer patients have significant co‐morbidity. The aim of this study was to investigate whether there were associations between co‐morbidity and muscle measures in patients with advanced non‐small cell lung cancer.
Methods
Patients in a Phase III trial comparing two chemotherapy regimens in advanced non‐small cell lung cancer were analysed (n = 436). Co‐morbidity was assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS‐G), which rates co‐morbidity from 0 to 4 on 14 different organ scales. Severe co‐morbidity was defined as having any grades 3 and 4 CIRS‐G score. Muscle measures were assessed from baseline computed tomography slides at the L3 level using the Slice
OMatic software.
Results
Complete data were available for 263 patients (60%). Median age was 66, 57.0% were men, 78.7% had performance status 0–1, 25.9% Stage IIIB, 11.4% appetite loss, 92.4% were current/former smokers, 22.8% were underweight, 43.7% had normal weight, 26.6% were overweight, and 6.8% obese. The median total CIRS‐G score was 7 (range: 0–16), and 48.2% had severe co‐morbidity. Mean SMI was 44.7 cm2/m2 (range: 27–71), and the mean SMD was 37.3 Hounsfield units (HU) (range: 16–60). When comparing patients with and without severe co‐morbidity, there were no significant differences in median SMI (44.5 vs. 44.1 cm2/m2; 0.70), but patients with severe co‐morbidity had a significantly lower median SMD (36 HU vs. 39 HU; 0.001), mainly due to a significant difference in SMD between those with severe heart disease and those without (32.5 vs. 37.9 HU; 0.002). Linear regression analyses confirmed the association between severe co‐morbidity and SMD both in the simple analysis (0.001) and the multiple analysis (0.037) adjusting for baseline characteristics. Stage of disease, gender, and body mass index (BMI) were significantly associated with SMI in both the simple and multiple analyses. Age and BMI were significantly associated with SMD in the simple analysis; and age, gender, and BMI were significantly associated in the multiple analysis.
Conclusions
There were no significant differences in SMI between patients with and patients without severe co‐morbidity, but patients with severe co‐morbidity had lower SMD than other patients, mainly due to severe heart disease. Co‐morbidity might be a confounder in studies of the clinical role of SMD in cancer patients.

Macrophages protect against loss of adipose tissue during cancer cachexia

18-07-2019 – Merve Erdem, Diana Möckel, Sandra Jumpertz, Cathleen John, Athanassios Fragoulis, Ines Rudolph, Johanna Wulfmeier, Jochen Springer, Henrike Horn, Marco Koch, Georg Lurje, Twan Lammers, Steven Olde Damink, Gregory Kroft, Felix Gremse, Thorsten Cramer

Journal Article

Abstract
Background
Cancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti‐inflammatory drugs failed to show distinct cachexia‐inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)‐associated cachexia.
Methods
A transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell‐mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro‐inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care.
Results
We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography‐based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell‐mediated inflammation defect resulted in reduced expression of pro‐inflammatory cytokines in the serum of HCC‐bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia‐associated fat loss. Defective myeloid cell‐mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer‐induced fat loss.
Conclusions
Myeloid cell‐mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer‐induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti‐inflammatory drugs.

Muscle‐specific changes in protein synthesis with aging and reloading after disuse atrophy

16-07-2019 – Benjamin F. Miller, Leslie M. Baehr, Robert V. Musci, Justin J. Reid, Frederick F. Peelor, Karyn L. Hamilton, Sue C. Bodine

Journal Article

Abstract
Background
Successful strategies to halt or reverse sarcopenia require a basic understanding of the factors that cause muscle loss with age. Acute periods of muscle loss in older individuals have an incomplete recovery of muscle mass and strength, thus accelerating sarcopenic progression. The purpose of the current study was to further understand the mechanisms underlying the failure of old animals to completely recover muscle mass and function after a period of hindlimb unloading.
Methods
Hindlimb unloading was used to induce muscle atrophy in Fischer 344–Brown Norway (F344BN F1) rats at 24, 28, and 30 months of age. Rats were hindlimb unloaded for 14 days and then reloaded at 24 months (Reloaded 24), 28 months (Reloaded 28), and 24 and 28 months (Reloaded 24/28) of age. Isometric torque was determined at 24 months of age (24 months), at 28 months of age (28 months), immediately after 14 days of reloading, and at 30 months of age (30 months). During control or reloaded conditions, rats were labelled with deuterium oxide (D2O) to determine rates of muscle protein synthesis and RNA synthesis.
Results
After 14 days of reloading, in vivo isometric torque returned to baseline in Reloaded 24, but not Reloaded 28 and Reloaded 24/28. Despite the failure of Reloaded 28 and Reloaded 24/28 to regain peak force, all groups were equally depressed in peak force generation at 30 months. Increased age did not decrease muscle protein synthesis rates, and in fact, increased resting rates of protein synthesis were measured in the myofibrillar fraction (Fractional synthesis rate (FSR): %/day) of the plantaris (24 months: 2.53 ± 0.17; 30 months: 3.29 ± 0.17), and in the myofibrillar (24 months: 2.29 ± 0.07; 30 months: 3.34 ± 0.11), collagen (24 months: 1.11 ± 0.07; 30 months: 1.55 ± 0.14), and mitochondrial (24 months: 2.38 ± 0.16; 30 months: 3.20 ± 0.10) fractions of the tibialis anterior (TA). All muscles increased myofibrillar protein synthesis (%/day) in Reloaded 24 (soleus: 3.36 ± 0.11, 5.23 ± 0.19; plantaris: 2.53 ± 0.17, 3.66 ± 0.07; TA: 2.29 ± 0.14, 3.15 ± 0.12); however, in Reloaded 28, only the soleus had myofibrillar protein synthesis rates (%/day) >28 months (28 months: 3.80 ± 0.10; Reloaded 28: 4.86 ± 0.19). Across the muscles, rates of protein synthesis were correlated with RNA synthesis (all muscles combined, R2 = 0.807, P < 0.0001).
Conclusions
These data add to the growing body of literature that indicate that changes with age, including following disuse atrophy, differ by muscle. In addition, our findings lead to additional questions of the underlying mechanisms by which some muscles are maintained with age while others are not.

Comment on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al.

15-07-2019 – Yeshun Wu, Bin Zhu, Zijun Chen, Jiahao Duan, Ling Yang

Letter

Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa

15-07-2019 – Raquel G.F. Costa, Paula L. Caro, Emídio M. Matos‐Neto, Joanna D.C.C. Lima, Katrin Radloff, Michele J. Alves, Rodolfo G. Camargo, Ana Flávia M. Pessoa, Estefania Simoes, Patrícia Gama, Denise C. Cara, Aloísio S.F. Silva, Welbert O. Pereira, Linda F. Maximiano, Paulo S.M. Alcântara, José P. Otoch, Giorgio Trinchieri, Alessandro Laviano, Maurizio Muscaritoli, Marília Seelaender

Journal Article

Abstract
Background
Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia‐related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour.
Methods
Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® x
MAP) analyses.
Results
There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL‐6) and IL‐8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL‐7, IL‐13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte‐colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL‐13 and transforming growth factor beta 3.
Conclusions
The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.

Clinical and biological characterization of skeletal muscle tissue biopsies of surgical cancer patients

15-07-2019 – Ana Anoveros‐Barrera, Amritpal S. Bhullar, Cynthia Stretch, Nina Esfandiari, Abha R. Dunichand‐Hoedl, Karen J.B. Martins, David Bigam, Rachel G. Khadaroo, Todd McMullen, Oliver F. Bathe, Sambasivarao Damaraju, Richard J. Skipworth, Charles T. Putman, Vickie E. Baracos, Vera C. Mazurak

Journal Article

Abstract
Background
Researchers increasingly use intraoperative muscle biopsy to investigate mechanisms of skeletal muscle atrophy in patients with cancer. Muscles have been assessed for morphological, cellular, and biochemical features. The aim of this study was to conduct a state‐of‐the‐science review of this literature and, secondly, to evaluate clinical and biological variation in biopsies of rectus abdominis (RA) muscle from a cohort of patients with malignancies.
Methods
Literature was searched for reports on muscle biopsies from patients with a cancer diagnosis. Quality of reports and risk of bias were assessed. Data abstracted included patient characteristics and diagnoses, sample size, tissue collection and biobanking procedures, and results. A cohort of cancer patients (n = 190, 88% gastrointestinal malignancies), who underwent open abdominal surgery as part of their clinical care, consented to RA biopsy from the site of incision. Computed tomography (CT) scans were used to quantify total abdominal muscle and RA cross‐sectional areas and radiodensity. Biopsies were assessed for muscle fibre area (μm2), fibre types, myosin heavy chain isoforms, and expression of genes selected for their involvement in catabolic pathways of muscle.
Results
Muscle biopsy occurred in 59 studies (total N = 1585 participants). RA was biopsied intraoperatively in 40 studies (67%), followed by quadriceps (26%; percutaneous biopsy) and other muscles (7%). Cancer site and stage, % of male participants, and age were highly variable between studies. Details regarding patient medical history and biopsy procedures were frequently absent. Lack of description of the population(s) sampled and low sample size contributed to low quality and risk of bias. Weight‐losing cases were compared with weight stable cancer or healthy controls without considering a measure of muscle mass in 21 out of 44 studies. In the cohort of patients providing biopsy for this study, 78% of patients had preoperative CT scans and a high proportion (64%) met published criteria for sarcopenia. Fibre type distribution in RA was type I (46% ± 13), hybrid type I/IIA (1% ± 1), type IIA (36% ± 10), hybrid type IIA/D (15% ± 14), and type IID (2% ± 5). Sexual dimorphism was prominent in RA CT cross‐sectional area, mean fibre cross‐sectional area, and in expression of genes associated with muscle growth, apoptosis, and inflammation (P < 0.05). Medical history revealed multiple co‐morbid conditions and medications.
Conclusions
Continued collaboration between researchers and cancer surgeons enables a more complete understanding of mechanisms of cancer‐associated muscle atrophy. Standardization of biobanking practices, tissue manipulation, patient characterization, and classification will enhance the consistency, reliability, and comparability of future studies.

Physical function‐derived cut‐points for the diagnosis of sarcopenia and dynapenia from the Canadian longitudinal study on aging

15-07-2019 – Anne‐Julie Tessier, Simon S. Wing, Elham Rahme, José A. Morais, Stéphanie Chevalier

Journal Article

Abstract
Background
Aging is associated with sarcopenia (low muscle mass) and dynapenia (low muscle strength) leading to disability and mortality. Widely used previous cut‐points for sarcopenia were established from dated, small, or pooled cohorts. We aimed to identify cut‐points of low strength as a determinant of impaired physical performance and cut‐points of low appendicular lean mass (ALM) as a predictor of low strength in a single, large, and contemporary cohort of community‐dwelling older adults and compare these criteria with others.
Methods
Cross‐sectional analyses were conducted on baseline data from 4725 and 4363 community‐dwelling men and women (65–86 years, 96.8% Caucasian) of the Canadian longitudinal study on aging comprehensive cohort. Physical performance was evaluated from gait speed, timed up‐and‐go, chair rise, and balance tests; a weighted‐sum score was computed using factor analysis. Strength was measured by handgrip dynamometry; ALM, by dual‐energy X‐ray absorptiometry and ALM index (ALMI; kg/m2), was calculated. Classification and regression tree analyses determined optimal sex‐specific cut‐points of ALMI predicting low strength and of strength predicting impaired physical performance (score < 1.5 SD below the sex‐specific mean).
Results
Modest associations were found between ALMI and strength and between strength and physical performance score in both sexes. ALMI was not an independent predictor of physical performance score. Cut‐points of <33.1 and <20.4 kg were found to define dynapenia in men and in women, respectively, corresponding to 21.5% and 24.0% prevalence rates. Sarcopenia cut‐points were <7.76 kg/m2 in men and <5.72 kg/m2 in women; prevalence rates of 21.7% and 13.7%. Overall, 8.3% of men and 5.5% of women had sarco‐dynapenia. Sarcopenic were older and had lower fat mass and body mass index (BMI) than non‐sarcopenic participants. While the agreement between current criteria and the updated European Working Group for Sarcopenia in Older Persons recommendations was fair, we found only slight agreement with the Foundation for the National Institute of Health sarcopenia project. Older persons identified with sarcopenia as per the Foundation for the National Institute of Health criteria (using ALM/BMI as the index) have higher BMI and fat mass compared with non‐sarcopenic and have normal ALMI as per our criteria.
Conclusions
The proposed function‐derived cut‐points established from this single, large, and contemporary Canadian cohort should be used for the identification of sarcopenia and dynapenia in Caucasian older adults. We advise on using criteria based on ALMI in the diagnosis of sarcopenia. The modest agreement between sarcopenia and dynapenia denotes potential distinct health implications justifying to study both components separately.

Rapid atrophy of cardiac left ventricular mass in patients with non‐small cell carcinoma of the lung

10-07-2019 – Seyyed Mohammad Reza Kazemi‐Bajestani, Harald Becher, Charles Butts, Naveen S. Basappa, Michael Smylie, Anil Abraham Joy, Randeep Sangha, Andrea Gallivan, Peter Kavsak, Quincy Chu, Vickie E. Baracos

Journal Article

Abstract
Background
Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes.
Methods
Treatment naïve metastatic non‐small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin‐based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function LV ejection fraction, global longitudinal strain (GLS), diastolic function, computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival.
Results
During 112 ± 6 days, the median change in LVM was −8.9% 95% confidence interval (95% CI) −10.8 to −4.8, P < 0.001. Quartiles of LVM loss were −20.1%, −12.9%, −4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle odds ratio (OR) = 4.5, 95% CI: 1.4–14.8, P=0.01 and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7–36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9–22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C‐reactive protein (P=0.008), high sensitivity troponin T (hs‐Tn
T) (P=0.03), and galectin‐3 (P=0.02) increased over time, while N‐terminal pro B‐type natriuretic peptide and hs‐c
Tn
I did not change over time. C‐reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2–46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4–153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9–22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4–35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3–18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05).
Conclusions
Intense LVM atrophy is associated with non‐small cell lung cancer‐induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study.

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

08-07-2019 – Xiaoling Zhong, Marianne Pons, Christophe Poirier, Yanlin Jiang, Jianguo Liu, George E. Sandusky, Safi Shahda, Attila Nakeeb, C. Max Schmidt, Michael G. House, Eugene P. Ceppa, Nicholas J. Zyromski, Yunlong Liu, Guanglong Jiang, Marion E. Couch, Leonidas G. Koniaris, Teresa A. Zimmers

Journal Article

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice.
Methods
Isoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes.
Results
Murine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not.
Conclusions
Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

04-07-2019 – Joanna D.C.C. Lima, Estefania Simoes, Gabriela Castro, Mychel Raony P.T. Morais, Emidio M. Matos‐Neto, Michele J. Alves, Nelson I. Pinto, Raquel G. Figueredo, Telma M.T. Zorn, Aloísio S. Felipe‐Silva, Flavio Tokeshi, José P. Otoch, Paulo Alcantara, Fernanda J. Cabral, Emer S. Ferro, Alessandro Laviano, Marilia Seelaender

Journal Article

Abstract
Background
Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro‐environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro‐environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients.
Methods74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components.
Results
Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte–macrophage colony‐stimulating factor, interferon‐α, and interleukin (IL)‐8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight‐stable counterparts. Also, IL‐8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α‐smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)‐β1, TGF‐β2, and TGF‐β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen‐activated protein kinase alteration. Hypoxia‐inducible factor‐1α m
RNA content was significantly increased in the tumour of cachectic patients, when compared with weight‐stable group (P = 0.005).
Conclusions
Our results demonstrate TGF‐β pathway activation in the tumour in cachexia, through the (non‐canonical) mitogen‐activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF‐β‐induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

Changes in knee extension peak torque and body composition and their relationship with change in gait speed

04-07-2019 – Yusuke Osawa, Nancy Chiles Shaffer, Michelle D. Shardell, Stephanie A. Studenski, Luigi Ferrucci

Journal Article

Abstract
Background
Slow gait speed is a powerful predictor of disability in activities of daily living and mortality. Muscle strength and body composition change over time, but their changes differ by sex. How these parameters jointly affect gait speed decline is unknown. Understanding this association could help develop and evaluate the sex‐specific effects of lifestyle interventions to delay gait speed decline in older adults. We assessed whether changes in strength (Δstrength), appendicular lean mass (ΔALM), and fat mass (Δfat) jointly relate to change in gait speed and whether the association differs by sex.
Methods
The analytic sample comprised 575 women and 539 men aged 22–95 years enrolled in the Baltimore Longitudinal Study of Aging. Mean follow‐up was 4.0 years. Measures included isometric knee extension strength, dual‐energy X‐ray absorptiometry‐assessed ALM and fat mass, and gait speed from the 400 m fast pace walk. Sex‐specific linear mixed models were adjusted for follow‐up time and baseline age, race, height, ALM, fat mass, peak torque, and gait speed. We also included second‐order interaction terms of the key predictive variables (e.g. Δstrength × ΔALM). To interpret the interactions, we estimated average gait declines using the 25th or 75th percentile of the two significant predictive variables and then assessed which condition relates to larger decline in gait speed.
Results
In both sexes, independent of ΔALM and Δfat, larger decline in strength significantly related to larger decline in gait speed (P = 0.01 for both sexes). In men, interactions between Δstrength × ΔALM and Δfat by ΔALM were associated with change in gait speed; men with greater declines in both muscle strength and ALM or greater declines in both ALM and fat have steeper gait speed decline. In contrast, in women, the interaction between Δfat and ΔALM was associated with change in gait speed; women with an increase in fat mass combined with less decline in ALM have steeper gait speed decline.
Conclusions
While change in strength affects change in gait speed in both sexes, the effects of body composition change differ by sex. Dual‐energy X‐ray absorptiometry‐based estimates of lean mass may be confounded by intramuscular fat. Future studies should examine sex‐specific combined effects of change in strength and body composition on mobility using multiple techniques to measure body composition. Intervention studies should consider testing sex‐specific interventions on body composition.

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

21-06-2019 – Christian M. Girgis, Kuan Minn Cha, Benjamin So, Michael Tsang, Jennifer Chen, Peter J. Houweling, Aaron Schindeler, Rebecca Stokes, Michael M. Swarbrick, Frances J. Evesson, Sandra T. Cooper, Jenny E. Gunton

Journal Article

Abstract
Background
It has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte‐specific deletion of VDR would provide a strategy to answer this question.
Methods
Myocyte‐specific vitamin D receptor (m
VDR) null mice were generated by crossing human skeletal actin‐Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real‐time PCR.
Results
Unlike whole‐body VDR knockout mice, m
VDR mice showed a normal body size. The m
VDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel‐running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7–16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, m
VDR have increased proportional fat mass at 20% compared with 13%.
Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin‐dependent kinases Cdk‐2 and Cdk‐4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin m
RNA was lower in m
VDR muscle.
Conclusions
This study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.

The prognostic significance of weight loss in chronic obstructive pulmonary disease‐related cachexia: a prospective cohort study

17-06-2019 – Hoi Yee Kwan, Matthew Maddocks, Claire M. Nolan, Sarah E. Jones, Suhani Patel, Ruth E. Barker, Samantha S.C. Kon, Michael I. Polkey, Paul Cullinan, William D.‐C. Man

Journal Article

Abstract
Background
Cachexia is an important extra‐pulmonary manifestation of chronic obstructive pulmonary disease (COPD) presenting as unintentional weight loss and altered body composition. Previous studies have focused on the relative importance of body composition compared with body mass rather than the relative importance of dynamic compared with static measures. We aimed to determine the prevalence of cachexia and pre‐cachexia phenotypes in COPD and examine the associations between cachexia and its component features with all‐cause mortality.
Methods
We enrolled 1755 consecutive outpatients with stable COPD from two London centres between 2012 and 2017, stratified according to European Respiratory Society Task Force defined cachexia unintentional weight loss >5% and low fat‐free mass index (FFMI), pre‐cachexia (weight loss >5% but preserved FFMI), or no cachexia. The primary outcome was all‐cause mortality. We calculated hazard ratios (HRs) using Cox proportional hazards regression for cachexia classifications (cachexia, pre‐cachexia, and no cachexia) and component features (weight loss and FFMI) and mortality, adjusting for age, sex, body mass index, and disease‐specific prognostic markers.
Results
The prevalence of cachexia was 4.6% 95% confidence interval (CI): 3.6–5.6 and pre‐cachexia 1.6% (95% CI: 1.0–2.2). Prevalence was similar across sexes but increased with worsening Global Initiative for Chronic Obstructive Pulmonary Disease spirometric stage and Medical Research Council dyspnoea score (all P < 0.001). There were 313 (17.8%) deaths over a median (interquartile range) follow‐up duration 1089 (547–1704) days. Both cachexia HR 1.98 (95% CI: 1.31–2.99), P = 0.002 and pre‐cachexia HR 2.79 (95% CI: 1.48–5.29), P = 0.001 were associated with increased mortality. In multivariable analysis, the unintentional weight loss feature of cachexia was independently associated with mortality HR 2.16 (95% CI: 1.31–3.08), P < 0.001, whereas low FFMI was not HR 0.88 (95% CI: 0.64–1.20), P = 0.402. Sensitivity analyses using body mass index‐specific, age‐specific, and gender‐specific low FFMI values found consistent findings.
Conclusions
Despite the low prevalence of cachexia and pre‐cachexia, both confer increased mortality risk in COPD, driven by the unintentional weight loss component. Our data suggest that low FFMI without concurrent weight loss may not confer the poor prognosis as previously reported for this group. Weight loss should be regularly monitored in practice and may represent an important target in COPD management. We propose the incorporation of weight monitoring into national and international COPD guidance.

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

29-05-2019 – Volker Adams, T. Scott Bowen, Sarah Werner, Peggy Barthel, Christina Amberger, Anne Konzer, Johannes Graumann, Peter Sehr, Joe Lewis, Jan Provaznik, Vladimir Benes, Petra Büttner, Alexander Gasch, Norman Mangner, Christian C. Witt, Dittmar Labeit, Axel Linke, Siegfried Labeit

Journal Article

Abstract
Background
Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small‐molecule inhibitor of Mu
RF1 in treating CHF‐induced diaphragm myopathy and loss of contractile function.
Methods
Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham‐operated animals (sham) served as controls. One week post‐left anterior descending coronary artery ligation animals were randomized into two groups—one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946—a recently described Mu
RF1‐interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed.
Results
Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up‐regulation of the Mu
RF1 and Mu
RF2 was attenuated after infarct.
Conclusions
Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting Mu
RF1/Mu
RF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.

Association of lifestyle factors and inflammation with sarcopenic obesity: data from the PREDIMED‐Plus trial

29-05-2019 – Itziar Abete, Jadwiga Konieczna, M. Angeles Zulet, Aina M. Galmés‐Panades, Idoia Ibero‐Baraibar, Nancy Babio, Ramón Estruch, Josep Vidal, Estefanía Toledo, Cristina Razquin, Rafael Bartolomé, Andrés Díaz‐Lopez, Miquel Fiol, Rosa Casas, Josep Vera, Pilar Buil‐Cosiales, Xavier Pintó, Emili Corbella, Maria Puy Portillo, Jose Antonio Paz, Vicente Martín, Lidia Daimiel, Albert Goday, Nuria Rosique‐Esteban, Jordi Salas‐Salvadó, Dora Romaguera, J. Alfredo Martínez, on behalf of PREDIMED‐PLUS Investigators

Journal Article

Abstract
Background
Sarcopenia is a progressive age‐related skeletal muscle disorder associated with increased likelihood of adverse outcomes. Muscle wasting is often accompanied by an increase in body fat, leading to ‘sarcopenic obesity’. The aim of the present study was to analyse the association of lifestyle variables such as diet, dietary components, physical activity (PA), body composition, and inflammatory markers, with the risk of sarcopenic obesity.
Methods
A cross‐sectional analysis based on baseline data from the PREDIMED‐Plus study was performed. A total of 1535 participants (48% women) with overweight/obesity (body mass index: 32.5 ± 3.3 kg/m2; age: 65.2 ± 4.9 years old) and metabolic syndrome were categorized according to sex‐specific tertiles (T) of the sarcopenic index (SI) as assessed by dual‐energy X‐ray absorptiometry scanning. Anthropometrical measurements, biochemical markers, dietary intake, and PA information were collected. Linear regression analyses were carried out to evaluate the association between variables.
Results
Subjects in the first SI tertile were older, less physically active, showed higher frequency of abdominal obesity and diabetes, and consumed higher saturated fat and less vitamin C than subjects from the other two tertiles (all P < 0.05). Multiple adjusted linear regression models evidenced significant positive associations across tertiles of SI with adherence to the Mediterranean dietary score (P‐trend < 0.05), PA (P‐trend < 0.0001), and the 30 s chair stand test (P‐trend < 0.0001), whereas significant negative associations were found with an inadequate vitamin C consumption (P‐trend < 0.05), visceral fat and leucocyte count (all P‐trend < 0.0001), and some white cell subtypes (neutrophils and monocytes), neutrophil‐to‐lymphocyte ratio, and platelet count (all P‐trend < 0.05). When models were additionally adjusted by potential mediators (inflammatory markers, diabetes, and waist circumference), no relevant changes were observed, only dietary variables lost significance.
Conclusions
Diet and PA are important regulatory mediators of systemic inflammation, which is directly involved in the sarcopenic process. A healthy dietary pattern combined with exercise is a promising strategy to limit age‐related sarcopenia.

CT‐measured skeletal muscle mass used to assess frailty in patients with head and neck cancer

27-05-2019 – Aniek T. Zwart, Anouk Hoorn, Peter M.A. Ooijen, Roel J.H.M. Steenbakkers, Geertruida H. Bock, Gyorgy B. Halmos

Journal Article

Abstract
Background
Skeletal muscle depletion or sarcopenia is related to multiple adverse clinical outcome. However, frailty questionnaires are currently applied in the daily practice to identify patients who are potentially (un)suitable for treatment but are time consuming and straining for patients and the clinician. Screening for sarcopenia in patients with head and neck cancer (HNC) could be a promising fast biomarker for frailty. Our objective was to quantify sarcopenia with pre‐treatment low skeletal muscle mass from routinely obtained neck computed tomography scans at level of third cervical vertebra in patients diagnosed with HNC and evaluate its association with frailty.
Methods
A total of 112 HNC patients with Stages III and IV disease were included from a prospective databiobank. The amount of skeletal muscle mass was retrospectively defined using the skeletal muscle index (SMI). Correlation analysis between SMI and continuous frailty data and the observer agreement were analysed with Pearsons r correlation coefficients. Sarcopenia was present when SMI felt below previously published non‐gender specific thresholds (<43.2 cm2/m2). Frailty was evaluated by Geriatrics 8 (G8), Groningen Frailty Indicator, Timed Up and Go test, and Malnutrition Universal Screening Tool. A univariate and multivariate logistic regression analysis was performed for all patients and men separately to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs).
Results
The cohort included 82 men (73%) and 30 women (27%), with a total mean age of 63 (±9) years. The observer agreement for cross‐sectional measurements was excellent for both intra‐observer variability (r = 0.99, P < 0.001) and inter‐observer variability (r = 0.98, P < 0.001). SMI correlated best with G8 frailty score (r = 0.38, P < 0.001) and did not differ per gender. Sarcopenia was present in 54 (48%) patients, whereof 25 (46%) men and 29 (54%) women. Prevalence of frailty was between 5% and 54% depending on the used screening tool. The multivariate regression analysis for all patients and men separately isolated the G8 questionnaire as the only independent variable associated with sarcopenia (OR 0.76, 95% CI 0.66–0.89, P < 0.001 and OR 0.76, 95% CI 0.66–0.88, P < 0.001, respectively).
Conclusions
This is the first study that demonstrates that sarcopenia is independently associated with frailty based on the G8 questionnaire in HNC patients. These results suggest that in the future, screening for sarcopenia on routinely obtained neck computed tomography scans may replace time consuming frailty questionnaires and help to select the (un)suitable patients for therapy, which is highly clinically relevant.

Associations between sleep conditions and body composition states: results of the EPISONO study

24-05-2019 – “Ronaldo D. Piovezan, Camila Hirotsu, Renato Moizinho, Helton Sá Souza, Vania DAlmeida, Sergio Tufik, Dalva Poyares”

Journal Article

Abstract
Background
Evidence suggests anthropometric indicators of obesity are associated with changes in sleep quality and quantity, and the presence of obstructive sleep apnoea (OSA). Investigations including diverse and objective evaluations of sleep and body composition are scarce. We aimed to evaluate the associations between indicators of sleep impairment and body composition states in a sample from a population‐based study.
Methods
Participants of the first follow‐up of the EPISONO (São Paulo, Brazil) >50 years were cross‐sectionally evaluated. Sleep was assessed through questionnaires, actigraphy, and polysomnography. Body composition was evaluated by bioelectrical impedance analysis. Appendicular skeletal muscle mass adjusted for body mass index defined sarcopenia (men <0.789 and women <0.512). Total body fat defined obesity (men >30% and women >40%). The overlap between both conditions defined sarcopenic obesity (SO). Final results were obtained by multinomial logistic regression analysis.
Results
Three hundred fifty‐nine adults mean (standard deviation) age, 61 (8.8) years; 212 (59.1%) female were enrolled. Obesity was detected in 22.6% of the sample, sarcopenia in 5.6%, and SO in 16.2%. After controlling for covariates, OSA was associated with SO odds ratio = 3.14, 95% confidence interval (CI) = 1.49–6.61. Additionally, nocturnal hypoxaemia was associated with both obesity (adjusted odds ratio = 2.59, 95% CI = 1.49–4.49) and SO (odds ratio = 2.92, 95% CI = 1.39–6.13). Other indicators of poor sleep/sleep disorders were not associated with body composition states.
Conclusions
Sarcopenic obesity but not obesity alone was associated with OSA. Both obesity and SO but not sarcopenia were associated with nocturnal hypoxaemia. The findings suggest a complex pathophysiologic relationship between adverse body composition states and OSA. Upcoming research on risk factors and therapeutic interventions for OSA should target synchronically the lean and adipose body tissues.

Is muscle failure a better term than sarcopenia?

21-05-2019 – Charlotte Suetta, Andrea B. Maier

Letter

Appetite and food intake results from phase I studies of anamorelin

09-05-2019 – Robert A. Blum, Stuart Mair, Elizabeth M. Duus

Journal Article

Abstract
Background
Loss of appetite and body weight are potentially devastating, highly prevalent cancer complications. The ghrelin receptor is a mediator of appetite and metabolism, and anamorelin is a novel, orally administered ghrelin receptor agonist. Effects on appetite and food intake may influence body‐weight gain but can be difficult to measure in multi‐site studies. Here, we summarize two single‐centre trials.
Methods
Both trials were phase I, randomized, double‐blind, placebo‐controlled, partly/wholly crossover studies of healthy young adults. Study 102 tested single anamorelin doses of 1–20 mg. Assessments included post‐dose self‐ratings on 100 mm visual analogue scales for hunger, anticipated eating pleasure, and anticipated quantity of food consumption. Study 101 tested single 10, 25, and 50 mg doses. Assessments included the same scales plus caloric intake beginning 4 h post‐dose.
Results
Study 102 treated 16 male subjects (mean age, 26.3 years). Mean hunger scores generally increased after all treatments, with significant differences from placebo (P < 0.05) in the 5 mg anamorelin group at 0.5 and 1 h post‐dose (+8.2 and +13.2 mm). Results for other scales were similar. Study 101 treated nine male subjects (mean age, 26.3 years). Pooled findings for anamorelin 25 and 50 mg vs. placebo showed significant mean increases in hunger scores at all but 1 pre‐prandial time point, including the first assessment, 0.5 h post‐dose (+10.9 vs. +0.7 mm, P = 0.0077), and the last assessment, 4 h post‐dose (+32.7 vs. +7.0 mm, P = 0.0170), with a significant mean 18.4% increase vs. placebo in caloric intake (P = 0.0148).
Conclusions
In single‐centre studies of healthy adults, single anamorelin doses of 1–20 mg elicited modest increases in hunger, and single doses of 25 and 50 mg achieved significant increases in hunger and caloric intake. The findings are consistent with dose‐related weight gain reported in a prior phase I study as well as multi‐centre findings in cachectic cancer patients and expand the evidence supporting anamorelin as a potential intervention.

The clinical relevance of adiposity when assessing muscle health in men treated with androgen deprivation for prostate cancer

08-05-2019 – Patrick J. Owen, Robin M. Daly, Jack Dalla Via, Niamh L. Mundell, Patricia M. Livingston, Timo Rantalainen, Steve F. Fraser

Journal Article

Abstract
Background
Androgen deprivation therapy (ADT) for prostate cancer (PCa) may prospectively decrease absolute lean mass (LM) and increase absolute fat mass (FM). Given that estimates of LM by dual‐energy X‐ray absorptiometry may be overestimated in obese people, this study examined the influence of adiposity on muscle health in men treated with ADT for PCa.
Methods
This cross‐sectional study examined the influence of adiposity on total and appendicular LM (ALM), muscle cross‐sectional (CSA), and muscle strength in 70 men treated with ADT mean (standard deviation) age, 71 (6) years for PCa compared with age‐matched PCa (n = 52) and healthy controls (n = 70). Total body LM, FM and ALM, and 66% tibia and radius muscle CSA were quantified by dual‐energy X‐ray absorptiometry and peripheral quantitative computed tomography, respectively. ALM was further divided by height (m2) or body mass index, with muscle CSA expressed as a per cent of total limb CSA. Upper and lower body and back (three‐repetition maximum and dynamometry) muscle strength were expressed per kilogram of body weight.
Results
On average, ADT‐treated men had 4.4–6.4 kg greater FM compared with controls (P ≤ 0.014) and there were no differences in total body or ALM. Total body per cent LM and ALMBMI were 3.8–5.4% (P ≤ 0.001) and 7.8–9.4% (P ≤ 0.001) lower, respectively, in ADT‐treated men compared with both controls. Percentage muscle CSA at both sites and muscle strength (except leg) were 3.0–6.0% (P ≤ 0.031) and 15–17% (P ≤ 0.010) lower, respectively, in ADT‐treated men compared with both controls.
Conclusions
The findings from this study indicate muscle mass, size, and strength are compromised in men treated with ADT after accounting for their increased adiposity or body size.

Gait speed as a mediator of the effect of sarcopenia on dependency in activities of daily living

08-05-2019 – Miguel A. Perez‐Sousa, Luis Carlos Venegas‐Sanabria, Diego Andrés Chavarro‐Carvajal, Carlos Alberto Cano‐Gutierrez, Mikel Izquierdo, Jorge Enrique Correa‐Bautista, Robinson Ramírez‐Vélez

Journal Article

Abstract
Background
Sarcopenia in older adults is strongly associated with an increase in dependency in activities of daily living (ADL) and with a decline in gait speed. Interestingly, gait speed has been shown to independently predict mortality. In this context, our study aimed to explore the mediator role of gait speed on the relationship between sarcopenia and dependency in ADL.
Methods
A cross‐sectional study was conducted in Colombia, 19 705 older adults with a mean age of 70 years, 55.6% women, 16.1% with sarcopenia, and 14.7% mild, moderate, or severe dependency in ADL, according to ‘SABE Survey 2015’. Sarcopenia was assessed by calf circumference and ADL dependence through the Barthel Index. Gait speed was measured over a distance of 3 m. The association between sarcopenia condition and gait speed and dependency level was analysed by linear regression adjusted by covariates. To examine whether gait speed mediated the association between sarcopenia and dependence components of physical function, simple mediation models were generated using ordinary least squares with the macro PROCESS version 3.2, adjusted for age, sex, and body mass index (BMI).
Results
Significant differences (P < 0.05) were found in gait speed and dependency in ADL between the sarcopenia and non‐sarcopenia groups after adjusting for age, sex, and BMI. BMI was significantly higher in the non‐sarcopenia group whereas dependency was significantly higher in the sarcopenia group (19.6% vs. 13.8%). Results from mediation model regression analysis indicated a significant and direct detrimental effect of sarcopenia on dependency in ADL (β = −0.05; P < 0.001), and a significant indirect effect of gait speed on the direct effect (−0.009 to −0.004).
Conclusions
The negative effect of sarcopenia on functional dependence was mediated by the gait speed. Therefore, gait speed may positively influence the detrimental effect of sarcopenia for dependency, after adjusting for age, gender, and BMI. Consequently, physical exercise should be promoted and focused to circumvent the gait speed decline associated with age in older people with sarcopenia.

Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)

07-05-2019 – Pradeep Harish, Alberto Malerba, Ngoc Lu‐Nguyen, Leysa Forrest, Ornella Cappellari, Fanny Roth, Capucine Trollet, Linda Popplewell, George Dickson

Journal Article

Abstract
Background
Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset muscle disease affecting one per 80 000 of the general population characterized by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterized by increased fibrosis and atrophy. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to ameliorate symptoms in dystrophic muscles.
Methods
In this study, we performed a systemic delivery of a monoclonal antibody to immunologically block myostatin in the A17 mouse model of OPMD. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples.
Results
This treatment significantly (P < 0.01) improved body mass (11%) and muscle mass (for the tibialis anterior and extensor digitorum longus by 19% and 41%) in the A17 mice treated with RK35 when compared to saline controls. Similarly, a significantly (P < 0.01) increased muscle strength (18% increase in maximal tetanic force) and myofibre diameter (17% and 44% for the tibialis anterior and extensor digitorum longus), and reduced expression of markers of muscle fibrosis (40% reduction in area of expression), was also observed. No change in the density of intranuclear inclusions (a hallmark of disease progression of OPMD) was however observed.
Conclusions
Our study supports the clinical translation of such antibody‐mediated inhibition of myostatin as a treatment of OPMD. This strategy has implications to be used as adjuvant therapies with gene therapy based approaches, or to stabilize the muscle prior to myoblast transplantation.