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     Article first published online:  31 AUG 2017

Masakazu Saitoh, Junichi Ishida, Jochen Springer

Considering technique of assessment and method for normalizing skeletal muscle massno abstract

 

Saitoh, M., Ishida, J., and Springer, J. (2017) Considering technique of assessment and method for normalizing skeletal muscle mass. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12230.

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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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     Article first published online:  28 AUG 2017

Junichi Ishida, Masakazu Saitoh, Jochen Springer

Is cardiac wasting accompanied by skeletal muscle loss in breast cancer patients receiving anticancer treatment?no abstract

 

Ishida, J., Saitoh, M., and Springer, J. (2017) Is cardiac wasting accompanied by skeletal muscle loss in breast cancer patients receiving anticancer treatment?. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12229.

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     Article first published online:  28 AUG 2017

Jacob L. Brown, Megan E. Rosa-Caldwell, David E. Lee1, Thomas A. Blackwell, Lemuel A. Brown, Richard A. Perry, Wesley S. Haynie, Justin P. Hardee, James A. Carson, Michael P. Wiggs, Tyrone A. Washington, Nicholas P. Greenearks

Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing miceBackground
Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice.
Methods
First, weight-stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student–Newman–Kuels post hoc test.
Results
MinStable mice displayed ~50% lower Pgc-1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting.
Conclusions
Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.

 

Brown, J. L., Rosa-Caldwell, M. E., Lee, D. E., Blackwell, T. A., Brown, L. A., Perry, R. A., Haynie, W. S., Hardee, J. P., Carson, J. A., Wiggs, M. P., Washington, T. A., and Greene, N. P. (2017) Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12232.

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     Article first published online:  26 JUL 2017

Giorgos K. Sakellariou, Adam P. Lightfoot, Kate E. Earl, Martin Stofanko, Brian McDonagh

Redox homeostasis and age-related deficits in neuromuscular integrity and functionSkeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age-related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age-associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age-related muscle atrophy and weakness.

 

Sakellariou, G. K., Lightfoot, A. P., Earl, K. E., Stofanko, M., and McDonagh, B. (2017) Redox homeostasis and age-related deficits in neuromuscular integrity and function. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12223.

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     Article first published online:  20 JUL 2017

Katherine A. Michaelis, Xinxia Zhu, Kevin G. Burfeind, Stephanie M. Krasnow, Peter R. Levasseur, Terry K. Morgan, Daniel L. Marks

Establishment and characterization of a novel murine model of pancreatic cancer cachexiaBackground
Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse.
Methods
Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.
Results
All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone.
Conclusions
Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

 

Michaelis, K. A., Zhu, X., Burfeind, K. G., Krasnow, S. M., Levasseur, P. R., Morgan, T. K., and Marks, D. L. (2017) Establishment and characterization of a novel murine model of pancreatic cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12225.

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     Article first published online:  19 JUL 2017

Michael T. Paris, Benoit Lafleur, Joel A. Dubin, Marina Mourtzakis

Development of a bedside viable ultrasound protocol to quantify appendicular lean tissue massBackground
Ultrasound is a non-invasive and readily available tool that can be prospectively applied at the bedside to assess muscle mass in clinical settings. The four-site protocol, which images two anatomical sites on each quadriceps, may be a viable bedside method, but its ability to predict musculature has not been compared against whole-body reference methods. Our primary objectives were to (i) compare the four-site protocol's ability to predict appendicular lean tissue mass from dual-energy X-ray absorptiometry; (ii) optimize the predictability of the four-site protocol with additional anatomical muscle thicknesses and easily obtained covariates; and (iii) assess the ability of the optimized protocol to identify individuals with low lean tissue mass.
Methods
This observational cross-sectional study recruited 96 university and community dwelling adults. Participants underwent ultrasound scans for assessment of muscle thickness and whole-body dual-energy X-ray absorptiometry scans for assessment of appendicular lean tissue. Ultrasound protocols included (i) the nine-site protocol, which images nine anterior and posterior muscle groups in supine and prone positions, and (ii) the four-site protocol, which images two anterior sites on each quadriceps muscle group in a supine position.
Results
The four-site protocol was strongly associated (R2 = 0.72) with appendicular lean tissue mass, but Bland–Altman analysis displayed wide limits of agreement (-5.67, 5.67 kg). Incorporating the anterior upper arm muscle thickness, and covariates age and sex, alongside the four-site protocol, improved the association (R2 = 0.91) with appendicular lean tissue and displayed narrower limits of agreement (-3.18, 3.18 kg). The optimized protocol demonstrated a strong ability to identify low lean tissue mass (area under the curve = 0.89).
Conclusions
The four-site protocol can be improved with the addition of the anterior upper arm muscle thickness, sex, and age when predicting appendicular lean tissue mass. This optimized protocol can accurately identify low lean tissue mass, while still being easily applied at the bedside.

 

Paris, M. T., Lafleur, B., Dubin, J. A., and Mourtzakis, M. (2017) Development of a bedside viable ultrasound protocol to quantify appendicular lean tissue mass. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12213.

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     Article first published online:  15 JUL 2017

Audrey Loumaye, Marie de Barsy, Maxime Nachit, Pascale Lause, Aline van Maanen, Pierre Trefois, Damien Gruson, Jean-Paul Thissen

Circulating Activin A predicts survival in cancer patientsBackground
Several experimental evidences pinpoint the possible role of Activin A (ActA) as a driver of cancer cachexia. Supporting this hypothesis, we showed recently that human cancer cachexia is associated with high ActA levels. Moreover, ActA levels were correlated with body weight loss and skeletal muscle density, two prognostic factors in cancer patients. Our goal was therefore to investigate the value of ActA to predict survival in cancer patients.
Methods
Patients with colorectal or lung cancer were prospectively enrolled at the time of diagnosis or relapse between January 2012 and March 2014. At baseline, patients had clinical, nutritional, and functional assessment. Body composition and skeletal muscle density were measured by CT scan, and plasma ActA concentrations were determined. Overall survival (OS) was analysed since inclusion to 24 months later.
Results
Survival data were available for 149 patients out of 152. Patients with high ActA (=408 pg/mL) had lower OS than those with low levels, regardless the type of cancer (OS in colorectal cancer, 50% vs. 79%, P < 0.05; and in lung cancer, 27% vs. 67%, P = 0.001). The multivariable analysis confirmed the prognostic value of ActA independently of tumour stage or inflammatory markers, particularly in lung cancer. Low muscularity was also an independent prognostic factor.
Conclusions
Our study demonstrates that high ActA level is an independent prognosis factor of survival in cancer patients. More than a basic marker of the severity of the neoplastic disease or of the inflammatory process, ActA seems to influence survival by contributing to the development of cachexia and loss of skeletal muscle mass.

 

Loumaye, A., de Barsy, M., Nachit, M., Lause, P., van Maanen, A., Trefois, P., Gruson, D., and Thissen, J.-P. (2017) Circulating Activin A predicts survival in cancer patients. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12209.

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     Article first published online:  12 JUL 2017

Willemke Nijholt, Aldo Scafoglieri, Harriët Jager-Wittenaar, Johannes S.M. Hobbelen, Cees P. van der Schans

The reliability and validity of ultrasound to quantify muscles in older adults: a systematic reviewThis review evaluates the reliability and validity of ultrasound to quantify muscles in older adults. The databases PubMed, Cochrane, and Cumulative Index to Nursing and Allied Health Literature were systematically searched for studies. In 17 studies, the reliability (n = 13) and validity (n = 8) of ultrasound to quantify muscles in community-dwelling older adults (=60 years) or a clinical population were evaluated. Four out of 13 reliability studies investigated both intra-rater and inter-rater reliability. Intraclass correlation coefficient (ICC) scores for reliability ranged from -0.26 to 1.00. The highest ICC scores were found for the vastus lateralis, rectus femoris, upper arm anterior, and the trunk (ICC = 0.72 to 1.000). All included validity studies found ICC scores ranging from 0.92 to 0.999. Two studies describing the validity of ultrasound to predict lean body mass showed good validity as compared with dual-energy X-ray absorptiometry (r2 = 0.92 to 0.96). This systematic review shows that ultrasound is a reliable and valid tool for the assessment of muscle size in older adults. More high-quality research is required to confirm these findings in both clinical and healthy populations. Furthermore, ultrasound assessment of small muscles needs further evaluation. Ultrasound to predict lean body mass is feasible; however, future research is required to validate prediction equations in older adults with varying function and health.

 

Nijholt, W., Scafoglieri, A., Jager-Wittenaar, H., Hobbelen, J. S. M., and van der Schans, C. P. (2017) The reliability and validity of ultrasound to quantify muscles in older adults: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12210.

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     Article first published online:  3 JUL 2017

Vered Raz, Yotam Raz, Guillem Paniagua-Soriano, Jacomina Cornelia Roorda, Cyriel Olie, Muhammad Riaz, Bogdan I. Florea

Proteasomal activity-based probes mark protein homeostasis in musclesBackground
Protein homeostasis, primarily regulated by the ubiquitin–proteasome system is crucial for proper function of cells. In tissues of post-mitotic cells, the impaired ubiquitin–proteasome system is found in a wide range of neuromuscular disorders. Activity-based probes (ABPs) measure proteasomal proteolytic subunits and can be used to report protein homeostasis. Despite the crucial role of the proteasome in neuromuscular pathologies, ABPs were not employed in muscle cells and tissues, and measurement of proteasomal activity was carried out in vitro using low-throughput procedures.
Methods
We screened six ABPs for specific application in muscle cell culture using high throughput call-based imaging procedures. We then determined an in situ proteasomal activity in myofibers of muscle cryosections.
Results
We demonstrate that LWA300, a pan-reactive proteasomal probe, is most suitable to report proteasomal activity in muscle cells using cell-based bio-imaging. We found that proteasomal activity is two-fold and three-fold enhanced in fused muscle cell culture compared with non-fused cells. Moreover, we found that proteasomal activity can discriminate between muscles. Across muscles, a relative higher proteasomal activity was found in hybrid myofibers whereas fast-twitch myofibers displayed lower activity.
Conclusions
Our study demonstrates that proteasomal activity differ between muscles and between myofiber types. We suggest that ABPs can be used to report disease progression and treatment efficacy.

 

Raz, V., Raz, Y., Paniagua-Soriano, G., Roorda, J. C., Olie, C., Riaz, M., and Florea, B. I. (2017) Proteasomal activity-based probes mark protein homeostasis in muscles. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12211.

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     Article first published online:  3 JUL 2017

Tania Cid-Díaz, Icía Santos-Zas, Jessica González-Sánchez, Uxía Gurriarán-Rodríguez, Carlos S. Mosteiro, Xesús Casabiell, Tomás García-Caballero, Vincent Mouly, Yolanda Pazos1, Jesús P. Camiña

Obestatin controls the ubiquitin–proteasome and autophagy–lysosome systems in glucocorticoid-induced muscle cell atrophyBackground
Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid-induced and wasting disorder-related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid-induced muscle cell atrophy.
Methods
In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes.
Results
The activation of the obestatin/GPR39 system protects from glucocorticoid-induced atrophy by regulation of Akt, PKD/PKCµ, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin–proteasome system and autophagy–lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post-translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes.
Conclusions
Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions.

 

Cid-Díaz, T., Santos-Zas, I., González-Sánchez, J., Gurriarán-Rodríguez, U., Mosteiro, C. S., Casabiell, X., García-Caballero, T., Mouly, V., Pazos, Y., and Camiña, J. P. (2017) Obestatin controls the ubiquitin–proteasome and autophagy–lysosome systems in glucocorticoid-induced muscle cell atrophy. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12222.

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     Article first published online:  3 JUL 2017

Pablo Molina, Juan J. Carrero, Jordi Bover, Philippe Chauveau, Sandro Mazzaferro, Pablo Ureña Torres and for the European Renal Nutrition (ERN) and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Working Groups of the European Renal Association–European Dialysis Transplant Association (ERA-EDTA)

Vitamin D, a modulator of musculoskeletal health in chronic kidney diseaseThe spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non-genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25-hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

 

Molina, P., Carrero, J. J., Bover, J., Chauveau, P., Mazzaferro, S., Torres, P. U., and for the European Renal Nutrition (ERN) and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Working Groups of the European Renal Association–European Dialysis Transplant Association (ERA-EDTA) (2017) Vitamin D, a modulator of musculoskeletal health in chronic kidney disease. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12218.

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     Article first published online:  18 JUN 2017

Ola Magne Vagnildhaug, David Blum, Andrew Wilcock, Peter Fayers, Florian Strasser, Vickie E. Baracos, Marianne J. Hjermstad, Stein Kaasa, Barry Laird, Tora S. Solheim and for the European Palliative Care Cancer Symptom study group

The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysisBackground
A body mass index (BMI) adjusted weight loss grading system (WLGS) is related to survival in patients with cancer. The aim of this study was to examine the applicability of the WLGS by confirming its prognostic validity, evaluating its relationship to cachexia domains, and exploring its ability to predict cachexia progression.
Methods
An international, prospective observational study of patients with incurable cancer was conducted. For each patient, weight loss grade was scored 0–4. Weight loss grade 0 represents a high BMI with limited weight loss, progressing through to weight loss grade 4 representing low BMI and a high degree of weight loss. Survival analyses were used to confirm prognostic validity. Analyses of variance were used to evaluate the relationship between the WLGS and cachexia domains [anorexia, dietary intake, Karnofsky performance status (KPS), and physical and emotional functioning]. Cox regression was used to evaluate if the addition of cachexia domains to the WLGS improved prognostic accuracy. Predictive ability of cachexia progression was assessed by estimating proportion of patients progressing to a more advanced weight loss grade.
Results
One thousand four hundred six patients were analysed (median age 66 years; 50% female, 63% KPS = 70). The overall effect of the WLGS on survival was significant as expressed by change in -2 log likelihood (P < 0.001) and persisted after adjustment for age, sex, and cancer type and stage (P < 0.001). Median survival decreased across the weight loss grades ranging from 407 days (95% CI 312–502)—weight loss grade 0 to 119 days (95% CI 93–145)—weight loss grade 4. All cachexia domains significantly deteriorated with increasing weight loss grade, and deterioration was greatest for dietary intake, with a difference corresponding to 0.87 standard deviations between weight loss grades 0 and 4. The addition of KPS, anorexia, and physical and emotional functioning improved the prognostic accuracy of the WLGS. Likelihood of cachexia progression was greater in patients with weight loss grade 2 (39%) than that with weight loss grade 0 (19%) or 1 (22%).
Conclusions
The WLGS is related to survival, cachexia domains, and the likelihood of progression. Adding certain cachexia domains to the WLGS improves prognostic accuracy.

 

Vagnildhaug, O. M., Blum, D., Wilcock, A., Fayers, P., Strasser, F., Baracos, V. E., Hjermstad, M. J., Kaasa, S., Laird, B., Solheim, T. S., and for the European Palliative Care Cancer Symptom study group (2017) The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12220.

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     Article first published online:  18 JUN 2017

Hiroki Nishikawa, Hirayuki Enomoto, Akio Ishii, Yoshinori Iwata, Yuho Miyamoto, Noriko Ishii, Yukihisa Yuri, Kunihiro Hasegawa, Chikage Nakano, Takashi Nishimura, Kazunori Yoh, Nobuhiro Aizawa, Yoshiyuki Sakai, Naoto Ikeda, Tomoyuki Takashima, Ryo Takata, Hiroko Iijima, Shuhei Nishiguchi

Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosisBackground
We aimed to elucidate the relationship between serum myostatin levels and other markers including skeletal muscle mass and to investigate the influence of serum myostatin levels on survival for patients with liver cirrhosis (LC).
Methods
A total of 198 LC subjects were analysed in this study. Myostatin levels were measured using stored sera. We retrospectively investigated the relationship between myostatin level and other markers, and the influence of myostatin level on overall survival (OS). Assessment of skeletal muscle mass was performed using the psoas muscle index (PMI) on computed tomography images at baseline. PMI indicates the sum of bilateral psoas muscle mass calculated by hand tracing at the lumber three level on computed tomography images divided by height squared (cm2/m2). The study cohort was divided into two groups based on the median myostatin value in each gender.
Results
Our study cohort included 108 male and 90 female patients with a median age of 67.5 years. The median (range) myostatin level for male patients was 3419.6 pg/mL (578.4–12897.7 pg/mL), whereas that for female patients was 2662.4 pg/mL (710.4–8782.0 pg/mL) (P = 0.0024). Median (range) serum myostatin level for Child–Pugh A patients (n = 123) was 2726.0 pg/mL (578.4–12667.2 pg/mL), whereas that for Child–Pugh B or C patients (n = 75) was 3615.2 pg/mL (663.3–12897.7 pg/mL) (P = 0.0011). For the entire cohort, the 1-, 3-, 5-, and 7-year cumulative OS rates were 93.94%, 72.71%, 50.37%, and 38.47%, respectively, in the high-myostatin group and 96.97%, 83.27%, 73.60%, and 69.95%, respectively, in the low-myostatin group (P = 0.0001). After excluding hepatocellular carcinoma patients (at baseline) from our analysis (n = 158), the 1-, 3-, 5-, and 7-year cumulative OS rates were 96.0%, 77.93%, 52.97%, and 39.08%, respectively, in the high-myostatin group and 96.39%, 87.58%, 77.63%, and 73.24%, respectively, in the low-myostatin group (P = 0.0005). Higher age (P = 0.0111) and lower PMI (P < 0.0001) were identified as significant predictors of poorer OS in our multivariate analysis, while higher serum myostatin (P = 0.0855) tended to be a significant adverse predictor. In both genders, PMI, serum albumin, prothrombin time, and branched-chain amino acid to tyrosine ratio showed a significantly inverse correlation with myostatin levels, and serum ammonia levels showed a significantly positive correlation with myostatin levels.
Conclusions
Higher serum myostatin levels correlated with muscle mass loss, hyperammonemia, and impaired protein synthesis, as reflected by lower serum albumin levels and lower branched-chain amino acid to tyrosine ratio levels. High serum myostatin levels were also associated with a reduced OS rate in LC patients.

 

Nishikawa, H., Enomoto, H., Ishii, A., Iwata, Y., Miyamoto, Y., Ishii, N., Yuri, Y., Hasegawa, K., Nakano, C., Nishimura, T., Yoh, K., Aizawa, N., Sakai, Y., Ikeda, N., Takashima, T., Takata, R., Iijima, H., and Nishiguchi, S. (2017) Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12212.

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     Article first published online:  14 JUN 2017

Tora S. Solheim, Barry J.A. Laird, Trude Rakel Balstad, Guro B . Stene,AstaBye, Neil Johns,Caroline H. Pettersen, Marie Fallon, Peter Fayers, Kenneth Fearon, Stein Kaasa

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancerBackground
Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n-3 polyunsaturated fatty acid nutritional supplements, exercise, and anti-inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy.
Methods
Patients receiving two cycles of standard chemotherapy were randomized to either the multimodal cachexia intervention or standard care. Primary outcome measures were feasibility assessed by recruitment, attrition, and compliance with intervention (>50% of components in >50% of patients). Key secondary outcomes were change in weight, muscle mass, physical activity, safety, and survival.
Results
Three hundred and ninety-nine were screened resulting in 46 patients recruited (11.5%). Twenty five patients were randomized to the treatment and 21 as controls. Forty-one completed the study (attrition rate 11%). Compliance to the individual components of the intervention was 76% for celecoxib, 60% for exercise, and 48% for nutritional supplements. As expected from the sample size, there was no statistically significant effect on physical activity or muscle mass. There were no intervention-related Serious Adverse Events and survival was similar between the groups.
Conclusions
A multimodal cachexia intervention is feasible and safe in patients with incurable lung or pancreatic cancer; however, compliance to nutritional supplements was suboptimal. A phase III study is now underway to assess fully the effect of the intervention.

 

Solheim, T. S., Laird, B. J. A., Balstad, T. R., Stene, G. B., Bye, A., Johns, N., Pettersen, C. H., Fallon, M., Fayers, P., Fearon, K., and Kaasa, S. (2017) A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12201.

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     Article first published online:  12 JUN 2017

Coby van de Bool, Erica P.A. Rutten, Ardy van Helvoort, Frits M.E. Franssen, Emiel F.M. Wouters, Annemie M.W.J. Schols

A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPDBackground
Evidence regarding the efficacy of nutritional supplementation to enhance exercise training responses in COPD patients with low muscle mass is limited.
The objective was to study if nutritional supplementation targeting muscle derangements enhances outcome of exercise training in COPD patients with low muscle mass.
Methods
Eighty-one COPD patients with low muscle mass, admitted to out-patient pulmonary rehabilitation, randomly received oral nutritional supplementation, enriched with leucine, vitamin D, and omega-3 fatty acids (NUTRITION) or PLACEBO as adjunct to 4 months supervised high intensity exercise training.
Results
The study population (51% males, aged 43–80) showed moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. Intention-to-treat analysis revealed significant differences after 4 months favouring NUTRITION for body mass (mean difference ± SEM) (+1.5 ± 0.6 kg, P = 0.01), plasma vitamin D (+24%, P = 0.004), eicosapentaenoic acid (+91%,P < 0.001), docosahexaenoic acid (+31%, P < 0.001), and steps/day (+24%, P = 0.048). After 4 months, both groups improved skeletal muscle mass (+0.4 ± 0.1 kg, P < 0.001), quadriceps muscle strength (+12.3 ± 2.3 Nm,P < 0.001), and cycle endurance time (+191.4 ± 34.3 s, P < 0.001). Inspiratory muscle strength only improved in NUTRITION (+0.5 ± 0.1 kPa, P = 0.001) and steps/day declined in PLACEBO (-18%,P = 0.005).
Conclusions
High intensity exercise training is effective in improving lower limb muscle strength and exercise performance in COPD patients with low muscle mass and moderate airflow obstruction. Specific nutritional supplementation had additional effects on nutritional status, inspiratory muscle strength, and physical activity compared with placebo.

 

van de Bool, C., Rutten, E. P. A., van Helvoort, A., Franssen, F. M. E., Wouters, E. F. M., and Schols, A. M. W. J. (2017) A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPD. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12219.

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     Article first published online:  12 JUN 2017

Yuki Enoki, Hiroshi Watanabe, Riho Arake, Rui Fujimura, Kana Ishiodori, Tadashi Imafuku, Kento Nishida, Ryusei Sugimoto, Saori Nagao, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama

Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunctionBackground
Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.
Methods
The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6-nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non-treatment group and AST-120, L-carnitine, or teneligliptin treatment groups.
Results
In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1a and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co-incubation with an anti-oxidant, ascorbic acid, L-carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin-6 and atrophy-related factors such as myostatin and atrogin-1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG-1a and increased muscular autophagy, as reflected by decreased mitochondria-rich type I fibres. An AST-120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L-carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.
Conclusions
Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS-targeted and mitochondria-targeted interventions for treating CKD-induced muscle atrophy and decreased exercise endurance.

 

Enoki, Y., Watanabe, H., Arake, R., Fujimura, R., Ishiodori, K., Imafuku, T., Nishida, K., Sugimoto, R., Nagao, S., Miyamura, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M., and Maruyama, T. (2017) Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12202.

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     Article first published online:  12 JUN 2017

Yuki Enoki, Hiroshi Watanabe, Riho Arake, Rui Fujimura, Kana Ishiodori, Tadashi Imafuku, Kento Nishida, Ryusei Sugimoto, Saori Nagao, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama

Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunctionBackground
Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.
Methods
The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6-nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non-treatment group and AST-120, L-carnitine, or teneligliptin treatment groups.
Results
In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1a and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co-incubation with an anti-oxidant, ascorbic acid, L-carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin-6 and atrophy-related factors such as myostatin and atrogin-1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG-1a and increased muscular autophagy, as reflected by decreased mitochondria-rich type I fibres. An AST-120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L-carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.
Conclusions
Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS-targeted and mitochondria-targeted interventions for treating CKD-induced muscle atrophy and decreased exercise endurance.

 

Enoki, Y., Watanabe, H., Arake, R., Fujimura, R., Ishiodori, K., Imafuku, T., Nishida, K., Sugimoto, R., Nagao, S., Miyamura, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M., and Maruyama, T. (2017) Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12202.

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     Article first published online:  10 MAY 2017

Asta Bye, Bjørg Sjøblom, Tore Wentzel-Larsen, Bjørn H. Grønberg, Vickie E. Baracos, Marianne J. Hjermstad, Nina Aass, Roy M. Bremnes, Øystein Fløtten, Marit Jordhøy

Muscle mass and association to quality of life in non-small cell lung cancer patientsBackground
Cancer wasting is characterized by muscle loss and may contribute to fatigue and poor quality of life (QoL). Our aim was to investigate associations between skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) and selected QoL outcomes in advanced non-small cell lung cancer (NSCLC) at diagnosis.
Methods
Baseline data from patients with stage IIIB/IV NSCLC and performance status 0–2 enrolled in three randomized trials of first-line chemotherapy (n = 1305) were analysed. Associations between SMI (cm2/m2) and SMD (Hounsfield units) based on computed tomography-images at the third lumbar level and self-reported physical function (PF), role function (RF), global QoL, fatigue, and dyspnoea were investigated by linear regression using flexible non-linear modelling.
Results
Complete data were available for 734 patients, mean age 65 years. Mean SMI was 47.7 cm2/m2 in men (n = 420) and 39.6 cm2/m2 in women (n = 314). Low SMI values were non-linearly associated with low PF and RF (men P = 0.016/0.020, women P = 0.004/0.012) and with low global QoL (P = 0.001) in men. Low SMI was significantly associated with high fatigue (P = 0.002) and more pain (P = 0.015), in both genders, but not with dyspnoea. All regression analyses showed poorer physical outcomes below an SMI breakpoint of about 42–45 cm2/m2 for men and 37–40 cm2/m2 for women. In both genders, poor PF and more dyspnoea were significantly associated with low SMD.
Conclusions
Low muscle mass in NSCLC negatively affects the patients' PF, RF, and global QoL, possibly more so in men than in women. However, muscle mass must be below a threshold value before this effect can be detected.

 

Bye, A., Sjøblom, B., Wentzel-Larsen, T., Grønberg, B. H., Baracos, V. E., Hjermstad, M. J., Aass, N., Bremnes, R. M., Fløtten, Ø., and Jordhøy, M. (2017) Muscle mass and association to quality of life in non-small cell lung cancer patients. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12206.

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     Article first published online:  16 APR 2017

Zherong Xu, Xin Feng, Juan Dong, Zhong-Min Wang, Jingyun Lee, Cristina Furdui, Daniel Clark Files, Kristen M. Beavers, Stephen Kritchevsky, Carolanne Milligan, Jian-Ping Jin, Osvaldo Delbono and Tan Zhang

Cardiac troponin T and fast skeletal muscle denervation in ageingBackground
Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.
Methods
Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.
Results
Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ—again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ.
Conclusions
Cardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast-twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function.

 

Xu, Z., Feng, X., Dong, J., Wang, Z.-M., Lee, J., Furdui, C., Files, D. C., Beavers, K. M., Kritchevsky, S., Milligan, C., Jin, J.-P., Delbono, O., and Zhang, T. (2017) Cardiac troponin T and fast skeletal muscle denervation in ageing. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12204.

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     Article first published online:  5 APR 2017

Yong-Soo Lee, Ja-Yeon Kim, Kyung-Soo Oh, Seok Won Chung

Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in miceBackground
Fatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid-binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model.
Methods
In the RCT model, we evaluated the expression of FABP4 by qRT-PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia-inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively.
Results
FABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear-induced FABP4 expression was up-regulated by hypoxia. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1β. Hypoxia-induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment.
Conclusions
This study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.

 

Lee, Y.-S., Kim, J.-Y., Oh, K.-S., and Chung, S. W. (2017) Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice. Journal of Cachexia, Sarcopenia and Muscle, doi: 10.1002/jcsm.12203.

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