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     Article first published online:  4 DEC 2017

Daniel S. Mytelka, Li Li, Karin Benoit

Post-diagnosis weight loss as a prognostic factor in non-small cell lung cancerBackground
Cachexia and its most visible manifestation, weight loss, represent important poor prognostic factors for patients with non-small cell lung cancer. This work examines how severity of weight loss as an indicator of cachexia affects outcomes.
Methods
In a retrospective observational study of electronic medical records, patients with non-small cell lung cancer were monitored for weight loss from an initial assessment (within 2 months of index diagnosis) to a landmark at 5 months (at least 3 months after initial assessment). Patients who survived to the landmark were then followed to determine the association of baseline body mass index (BMI) and weight loss during the assessment period with outcomes. Patients were clustered to determine how BMI and weight loss related to survival as approximated by time of last appearance in the database, a strong proxy for time of death.
Results
Twelve thousand one hundred and one patients were divided into 5 cachexia risk groups based on a combination of weight loss and initial BMI. More severe groups demonstrated progressively worse outcomes, with the most severe group surviving for a median of 263 days (95% CI 254–274) from index and having a 1-year survival rate of 31%. The least severe group survived for a median of 825 days from index (95% CI 768–908) and had a 1-year survival rate of 78%. Cachexia risk group was a stronger predictor of survival than any baseline variable, including disease stage, performance status, or age.
Conclusions
In this study, we showed that increasing weight loss and, to a lesser extent, decreasing BMI, led to substantially worse outcomes for non-small cell lung cancer patients independent of other variables. We suggest risk score groups that provide an improved approach for identifying poor prognosis patients with the greatest need.

 

Mytelka, D. S., Li, L., and Benoit, K. (2017) Post-diagnosis weight loss as a prognostic factor in non-small cell lung cancer. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12253.

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     Article first published online:  28 NOV 2017

Julien Siracusa, Nathalie Koulmann, Sébastien Banzet

Circulating myomiRs: a new class of biomarkers to monitor skeletal muscle in physiology and medicineMicroRNAs (miRNA) are small non-coding RNAs that target mRNAs and are consequently involved in the post-transcriptional regulation of gene expression. Some miRNAs are ubiquitously expressed in tissue, while others are tissue-specific or tissue-enriched. miRNAs can be released by cells and are found in various biofluids, including serum and plasma. Thus, measuring miRNAs in the circulation may provide information on the originating tissue or cells. MyomiRs are described as striated muscle-specific or muscle-enriched miRNAs. Their circulating levels can be measured and have been proposed to be new biomarkers of physiological and pathological muscle processes. The aims of this review are to summarize the current knowledge of circulating myomiRs, to identify the types of information they can provide about skeletal muscle, and to determine how to apply that information in the fields of research and medicine.

 

Siracusa, J., Koulmann, N., and Banzet, S. (2017) Circulating myomiRs: a new class of biomarkers to monitor skeletal muscle in physiology and medicine. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12227.

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     Article first published online:  21 NOV 2017

Alice Pannérec, Eugenia Migliavacca, Antonio De Castro, Joris Michaud, Sonia Karaz, Laurence Goulet, Serge Rezzi, Tze Pin Ng, Nabil Bosco, Anis Larbi, Jerome N. Feige

Vitamin B12 deficiency and impaired expression of amnionless during agingBackground
Physical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age-related chronic diseases, including in the musculo-skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models.
Methods
We analysed a subset of the Singapore Longitudinal Aging Study and stratified 238 participants based on age and Fried frailty criteria. Levels of methyl-malonic acid (MMA), a marker for vitamin B12 deficiency, and amnionless, the vitamin B12 co-receptor that anchors the vitamin B12 transport complex to the membrane of epithelial cells, were measured in plasma. In addition, vitamin B12 levels and the molecular mechanisms of vitamin B12 uptake and excretion were analysed in ileum, kidney, liver, and blood using a rat model of natural aging where nutritional intake is fully controlled.
Results
We demonstrate that aging and frailty are associated with a higher prevalence of functional vitamin B12 deficiency that can be detected by increased levels of MMA in blood (? = 0.25; P = 0.00013). The decline in circulating vitamin B12 levels is recapitulated in a rat model of natural aging where food composition and intake are stable. At the molecular level, these perturbations involve altered expression of amnionless in the ileum and kidney. Interestingly, we demonstrate that amnionless can be detected in serum where its levels increase during aging in both rodents and human (P = 3.3e-07 and 9.2e-07, respectively). Blood amnionless levels negatively correlate with vitamin B12 in rats (r2 = 0.305; P = 0.0042) and positively correlate with the vitamin B12 deficiency marker MMA in humans (? = 0.22; P = 0.00068).
Conclusions
Our results demonstrate that aging and frailty cause intrinsic vitamin B12 deficiencies, which can occur independently of nutritional intake. Mechanistically, vitamin B12 deficiency involves the physio-pathological decline of both the intestinal uptake and the renal reabsorption system for vitamin B12. Finally, amnionless is a novel biomarker which can detect perturbed vitamin B12 bioavailability during aging and physical frailty.

 

Song, M., Chen, F., Li, Y., Zhang, L., Wang, F., Qin, R., Wang, Z., Zhong, M., Tang, M., Zhang, W., and Han, L. (2017) Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12250.

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     Article first published online:  19 NOV 2017

Ming Song, Fang-fang Chen, Yi-hui Li, Lei Zhang, Feng Wang, Ran-ran Qin, Zhi-hao Wang, Ming Zhong, Meng-xiong Tang, Wei Zhang, Lu Han

Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injuryBackground
Exercise rehabilitation is demonstrated to improve the prognosis of patients with coronary heart disease (CHD). Statins, as the key medicine to lower cholesterol in CHD, result in skeletal muscle injury and impair exercise training adaptation. Energy metabolism dysfunction is identified as the potential mechanism underlying statin-induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin-associated exercise intolerance.
Methods
High-fat fed apolipoprotein E knockout (ApoE-/-) mice were given aerobic exercise and administrated simvastatin, trimetazidine, or simvastatin plus trimetazidine by gavage. Exercise capacity was evaluated at the end of the treatment by hanging grid test, forelimb grip strength, and running tolerance test. Plasma glucose, lipid, and creatine kinase concentrations were measured at the end of the treatment. After sacrifice, gastrocnemii were stored for assessment of muscle morphology and fibre type. Energy metabolism was estimated by plasma lactic acid concentration, ragged red fibres, and glycogen stores. Activities of mitochondrial complex III, citrate synthase activity, and membrane potential were measured to assess mitochondrial function. Oxidative stress was also evaluated by superoxide in mitochondria, superoxide dismutase activity, and glutathione redox state.
Results
In high-fat fed ApoE-/- mice, exercise training had no effect on lipid concentrations. Lower lipid concentrations with increased creatine kinase were observed with additional simvastatin treatment. Exercise capacity increased significantly in response to exercise training alone but was blunted by the addition of simvastatin. Similarly, cross-sectional area of muscle fibres and the proportion of slow-twitch fibres increased in the exercise group but decreased in the simvastatin plus exercise group. Additionally, simvastatin increased centronucleated fibres and induced energy metabolism dysfunction by inhibiting complex III activity and thus promoted oxidative stress in gastrocnemius. We demonstrated that trimetazidine could reverse simvastatin-induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast-to-slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine.
Conclusions
Trimetazidine alleviated statin-related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross-sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high-fat fed ApoE-/- mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid-lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins-induced exercise intolerance during cardiac rehabilitation in patients with CHD.

 

Song, M., Chen, F., Li, Y., Zhang, L., Wang, F., Qin, R., Wang, Z., Zhong, M., Tang, M., Zhang, W., and Han, L. (2017) Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12250.

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     Article first published online:  19 NOV 2017

Quan-Jun Yang, Jiang-Rong Zhao, Juan Hao, Bin Li, Yan Huo, Yong-Long Han, Li-Li Wan, Jie Li, Jinlu Huang, Jin Lu, Gen-Jin Yang, Cheng Guo

Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexiaBackground
Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance-based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model.
Methods
Eighty-four cancer cachexia patients, 33 pre-cachectic patients, 105 weight-stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model.
Results
Forty-six cancer cachexia patients, 22 pre-cachectic patients, 68 weight-stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre-cachectic patients, 37 weight-stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age-matched and sex-matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = −400.53 – 481.88 × log(Carnosine) −239.02 × log(Leucine) + 383.92 × log(Phenyl acetate), and the result showed 94.64% accuracy in the validation set.
Conclusions
This metabolomics study revealed a distinct metabolic profile of cancer cachexia and established and validated a diagnostic model. This research provided a feasible diagnostic tool for identifying at-risk populations through the detection of serum metabolites.

 

Yang, Q.-J., Zhao, J.-R., Hao, J., Li, B., Huo, Y., Han, Y.-L., Wan, L.-L., Li, J., Huang, J., Lu, J., Yang, G.-J., and Guo, C. (2017) Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12246.

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     Article first published online:  19 NOV 2017

Michael Tieland, Inez Trouwborst, Brian C. Clark

Skeletal muscle performance and ageingThe world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society, ~30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co-morbidity, and premature death. An important cause of physical limitations is the age-related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation–contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing.

 

Tieland, M., Trouwborst, I., and Clark, B. C. (2017) Skeletal muscle performance and ageing. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12238.

 

     Article first published online:  16 NOV 2017

Takashi Abe, Jeremy P. Loenneke, Robert S. Thiebaud

The use of ultrasound for the estimation of muscle mass: one site fits most?no abstract

 

Abe, T., Loenneke, J. P., and Thiebaud, R. S. (2017) The use of ultrasound for the estimation of muscle mass: one site fits most?. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12257.

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     Article first published online:  2 NOV 2017

Connie M. Rhee, Seyed-Foad Ahmadi, Csaba P. Kovesdy, Kamyar Kalantar-Zadeh

Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trialsBackground
Recent data pose the question whether conservative management of chronic kidney disease (CKD) by means of a low-protein diet can be a safe and effective means to avoid or defer transition to dialysis therapy without causing protein-energy wasting or cachexia. We aimed to systematically review and meta-analyse the controlled clinical trials with adequate participants in each trial, providing rigorous contemporary evidence of the impact of a low-protein diet in the management of uraemia and its complications in patients with CKD.
Methods
We searched MEDLINE (PubMed) and other sources for controlled trials on CKD to compare clinical management of CKD patients under various levels of dietary protein intake or to compare restricted protein intake with other interventions. Studies with similar patients, interventions, and outcomes were included in the meta-analyses.
Results
We identified 16 controlled trials of low-protein diet in CKD that met the stringent qualification criteria including having 30 or more participants. Compared with diets with protein intake of >0.8 g/kg/day, diets with restricted protein intake (<0.8 g/kg/day) were associated with higher serum bicarbonate levels, lower phosphorus levels, lower azotemia, lower rates of progression to end-stage renal disease, and a trend towards lower rates of all-cause death. In addition, very-low-protein diets (protein intake <0.4 g/kg/day) were associated with greater preservation of kidney function and reduction in the rate of progression to end-stage renal disease. Safety and adherence to a low-protein diet was not inferior to a normal protein diet, and there was no difference in the rate of malnutrition or protein-energy wasting.
Conclusions
In this pooled analysis of moderate-size controlled trials, a low-protein diet appears to enhance the conservative management of non-dialysis-dependent CKD and may be considered as a potential option for CKD patients who wish to avoid or defer dialysis initiation and to slow down the progression of CKD, while the risk of protein-energy wasting and cachexia remains minimal.

 

Rhee, C. M., Ahmadi, S.-F., Kovesdy, C. P., and Kalantar-Zadeh, K. (2017) Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trials. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12264.

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     Article first published online:  23 OCT 2017

Shinyu Ogasawara, Xian Wu Cheng, Aiko Inoue, Lina Hu, Limei Piao, Chenglin Yu, Hiroki Goto1, Wenhu Xu, Guangxian Zhao, Yanna Lei, Guang Yang, Kaoru Kimura, Hiroyuki Umegaki, Guo-Ping Shi, Masafumi Kuzuya

Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in miceBackground
Cathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non-enzymatic functions in signalling. Here, we examined whether CatK-deficiency (CatK−/−) would mitigate injury-related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis.
Methods
Cardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild-type (CatK+/+) and CatK−/− mice, and the mice were processed for morphological and biochemical studies.
Results
On post-injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK−/− reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2 and toll-like receptor-4, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. CatK deletion also restored the protein levels of caspase-3 and cleaved caspase-8 and the ratio of the BAX to the Bcl-2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK-specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase-3 proteins induced by CTX.
Conclusions
These results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.

 

Ogasawara, S., Cheng, X. W., Inoue, A., Hu, L., Piao, L., Yu, C., Goto, H., Xu, W., Zhao, G., Lei, Y., Yang, G., Kimura, K., Umegaki, H., Shi, G.-P., and Kuzuya, M. (2017) Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in mice. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12248.

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     Article first published online:  16 OCT 2017

Miriam van Dijk, Francina J. Dijk, Anita Hartog, Klaske van Norren, Sjors Verlaan, Ardy van Helvoort, Richard T. Jaspers, Yvette Luiking

Reduced dietary intake of micronutrients with antioxidant properties negatively impacts muscle health in aged miceBackground
Inadequate intake of micronutrients with antioxidant properties is common among older adults and has been associated with higher risk of frailty, adverse functional outcome, and impaired muscle health. However, a causal relationship is less well known. The aim was to determine in old mice the impact of reduced dietary intake of vitamins A/E/B6/B12/folate, selenium, and zinc on muscle mass, oxidative capacity, strength, and physical activity (PA) over time.
Methods
Twenty-one-month-old male mice were fed either AIN-93-M (control) or a diet low in micronutrients with antioxidant properties (=LOWOX-B: 50% of mouse recommended daily intake of vitamins A, E, B6, and B12, folate, selenium, and zinc) for 4 months. Muscle mass, grip strength, physical activity (PA), and general oxidative status were assessed. Moreover, muscle fatigue was measured of m. extensor digitorum longus (EDL) during an ex vivo moderate exercise protocol. Effects on oxidative capacity [succinate dehydrogenase (SDH) activity], muscle fibre type, number, and fibre cross-sectional area (fCSA) were assessed on m. plantaris (PL) using histochemistry.
Results
After 2 months on the diet, bodyweight of LOWOX-B mice was lower compared with control (P < 0.0001), mainly due to lower fat mass (P < 0.0001), without significant differences in food intake. After 4 months, oxidative status of LOWOX-B mice was lower, demonstrated by decreased vitamin E plasma levels (P < 0.05) and increased liver malondialdehyde levels (P = 0.018). PA was lower in LOWOX-B mice (P < 0.001 vs. control). Muscle mass was not affected, although PL-fCSA was decreased (~16%; P = 0.028 vs. control). SDH activity and muscle fibre type distribution remained unaffected. In LOWOX-B mice, EDL force production was decreased by 49.7% at lower stimulation frequencies (P = 0.038), and fatigue resistance was diminished (P = 0.023) compared with control.
Conclusions
Reduced dietary intake of vitamins A, E, B6, and B12, folate, selenium, and zinc resulted in a lower oxidative capacity and has major impact on muscle health as shown by decreased force production and PA, without effects on muscle mass. The reduced fCSA in combination with similar SDH activity per fibre might explain the reduced oxidative capacity resulting in the increased fatigue after exercise in LOWOX-B mice.

 

van Dijk, M., Dijk, F. J., Hartog, A., van Norren, K., Verlaan, S., van Helvoort, A., Jaspers, R. T., and Luiking, Y. (2017) Reduced dietary intake of micronutrients with antioxidant properties negatively impacts muscle health in aged mice. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12237.

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     Article first published online:  6 OCT 2017

Richard Paul, Jen Lee, Anna V. Donaldson, Martin Connolly, Mohammad Sharif, Samantha Amanda Natanek, Ulrich Rosendahl, Michael I. Polkey, Mark Griffiths, Paul R. Kemp

miR-422a suppresses SMAD4 protein expression and promotes resistance to muscle lossBackground
Loss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified.
Methods
The effect of miR-422a on SMAD4 expression and transforming growth factor (TGF)-β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross-sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU).
Results
miR-422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR-422a suppressed SMAD4 expression and inhibited TGF-beta and bone morphogenetic protein-dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU-associated muscle weakness, quadriceps expression of miR-422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively). Furthermore, pre-surgery levels of miR-422a were inversely associated with the amount of muscle that would be lost in the first post-operative week (r = −0.57, P < 0.001).
Conclusions
These data suggest that differences in miR-422a expression contribute to the susceptibility to muscle wasting associated with chronic and acute disease and that at least part of this activity may be mediated by reduced TGF-beta signalling in skeletal muscle.

 

Paul, R., Lee, J., Donaldson, A. V., Connolly, M., Sharif, M., Natanek, S. A., Rosendahl, U., Polkey, M. I., Griffiths, M., and Kemp, P. R. (2017) miR-422a suppresses SMAD4 protein expression and promotes resistance to muscle loss. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12236.

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     Article first published online: 6 OCT 2017

Ashok Narasimhan, Russell Greiner, Oliver F. Bathe, Vickie Baracos, Sambasivarao Damaraju

Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexiaBackground
Alternative splicing (AS) is a post-transcriptional gene regulatory mechanism that contributes to proteome diversity. Aberrant splicing mechanisms contribute to various cancers and muscle-related conditions such as Duchenne muscular dystrophy. However, dysregulation of AS in cancer cachexia (CC) remains unexplored. Our objectives were (i) to profile alternatively spliced genes (ASGs) on a genome-wide scale and (ii) to identify differentially expressed alternatively spliced genes (DASGs) associated with CC.
Methods
Rectus abdominis muscle biopsies obtained from cancer patients were stratified into cachectic cases (n = 21, classified based on International consensus diagnostic framework for CC) and non-cachectic controls (n = 19, weight stable cancer patients). Human transcriptome array 2.0 was used for profiling ASGs using the total RNA isolated from muscle biopsies. Representative DASG signatures were validated using semi-quantitative RT–PCR.
Results
We identified 8960 ASGs, of which 922 DASGs (772 up-regulated and 150 down-regulated) were identified at ≥1.4 fold-change and P < 0.05. Representative DASGs validated by semi-quantitative RT–PCR confirmed the primary findings from the human transcriptome arrays. Identified DASGs were associated with myogenesis, adipogenesis, protein ubiquitination, and inflammation. Up to 10% of the DASGs exhibited cassette exon (exon included or skipped) as a predominant form of AS event. We also observed other forms of AS events such as intron retention, alternate promoters.
Conclusions
Overall, we have, for the first time, conducted global profiling of muscle tissue to identify DASGs associated with CC. The mechanistic roles of the identified DASGs in CC pathophysiology using model systems is warranted, as well as replication of findings in independent cohorts.

 

Narasimhan, A., Greiner, R., Bathe, O. F., Baracos, V., and Damaraju, S. (2017) Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12235.

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     Article first published online:  10 SEP 2017

Philip C. Calder, Alessandro Laviano, Fredrik Lonnqvist, Maurizio Muscaritoli, Maria Öhlander, Annemie Schols

Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trialBackground
Cachectic patients with chronic obstructive pulmonary disease (COPD) may benefit from nutritional support. This double-blind, randomized, controlled trial evaluated the safety and efficacy of targeted medical nutrition (TMN) vs. an isocaloric comparator in pre-cachectic and cachectic patients with COPD.
Methods
Patients aged ≥50 years with moderate-to-severe COPD and involuntary weight loss or low body mass index (16–18 kg/m2) were randomized 1:1 to receive TMN (~230 kcal; 2 g omega-3 fatty acids; 10 μg 25-hydroxy-vitamin D3) or isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov Identifier: NCT02442908). Primary safety endpoints comprised adverse events and changes in vital signs, laboratory parameters, and concomitant medications. Secondary efficacy endpoints included changes in weight, body composition, exercise tolerance, metabolic biomarkers, and systemic inflammation.
Results
Forty-five patients were randomized to receive TMN (n = 22; mean 69.2 years) or isocaloric comparator (n = 23; mean 69.7 years). TMN was well tolerated. Adverse events were similar in number and type in both groups. Compliance to both products was good (TMN, 79%; comparator, 77%). Both groups gained weight, but the TMN group gained comparatively more fat mass (P = 0.0013). Reductions in systolic blood pressure (P = 0.0418) and secondary endpoints of triglycerides (P = 0.0217) and exercise-induced fatigue (P = 0.0223) and dyspnoea (P = 0.0382), and increases in high-density lipoprotein cholesterol (P = 0.0254), were observed in the TMN vs. the comparator group by week 12.
Conclusions
Targeted medical nutrition containing high-dose omega-3 fatty acids, vitamin D, and high-quality protein is well tolerated with a good safety profile and has positive effects on blood pressure and blood lipids and on exercise-induced fatigue and dyspnoea. Therefore, this TMN could be clinically beneficial in the nutritional and metabolic support of pre-cachectic and cachectic patients with COPD.

 

Calder, P. C., Laviano, A., Lonnqvist, F., Muscaritoli, M., Öhlander, M., and Schols, A. (2017) Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trial. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12228.

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     Article first published online:  28 AUG 2017

Moon Hyung Choi, Soon Nam Oh, In Kyu Lee, Seong Taek Oh, Daeyoun David Won

Sarcopenia is negatively associated with long-term outcomes in locally advanced rectal cancerBackground
The association of sarcopenia and visceral obesity to treatment outcome is not clear for locally advanced rectal cancer. This study evaluates the influence of skeletal muscle and visceral fat on short-term and long-term outcomes in locally advanced rectal cancer patients treated with neoadjuvant chemoradiation therapy followed by curative resection.
Methods
A total of 188 patients with locally advanced cancer were included between January 2009 and December 2013. Neoadjuvant chemoradiotherapy was followed by curative resection. Sarcopenia and visceral obesity were identified in initial staging CT by measuring the muscle and visceral fat area at the third lumbar vertebra level.
Results
Among the 188 included patients, 74 (39.4%) patients were sarcopenic and 97 (51.6%) patients were viscerally obese. Sarcopenia and high levels of preoperative carcinoembryonic antigen were significant prognostic factors for overall survival (P = 0.013, 0.014, respectively) in the Cox regression multivariate analysis. Visceral obesity was not associated with overall survival; however, it did tend to shorten disease-free survival (P = 0.079).
Conclusions
Sarcopenia is negatively associated with overall survival in locally advanced rectal cancer patients who underwent neoadjuvant chemoradiation therapy and curative resection. Visceral obesity tended to shorten disease-free survival. Future studies should be directed to optimize patient conditions according to body composition status.

 

Choi, M. H., Oh, S. N., Lee, I. K., Oh, S. T., and Won, D. D. (2017) Sarcopenia is negatively associated with long-term outcomes in locally advanced rectal cancer. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12234.

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