Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit?

Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008–2011)Journal of HepatologyVol. 63Issue 2PreviewAlthough sarcopaenia is associated with obesity-related comorbidities, its influence on non-alcoholic fatty liver disease (NAFLD) or steatohepatitis has not been fully determined. We aimed to investigate the direct relationship between sarcopaenia and NAFLD or steatohepatitis in the general population. Full-Text PDF Corrigendum to "Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit?" [J Hepatol 63 (2015) 309–311]Journal of HepatologyVol. 63Issue 5PreviewIn the 'Financial support' section of this manuscript one of the grants was incorrect. The correct version is presented below. Full-Text PDF There is exponential interest in non-alcoholic fatty liver disease (NAFLD) as a cause of chronic liver disease in the last decade [[1]Williams C.D. Stengel J. Asike M.I. Torres D.M. Shaw J. Contreras M. et al.Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.Gastroenterology. 2011; 140: 124-131Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar]. The epidemic of obesity due to changes in life style and nutritional habits in Western countries has greatly contributed to the rapid increase in prevalence of NAFLD. In addition to obesity, NAFLD is strongly associated with diabetes mellitus and insulin resistance that are believed to be a consequence of low physical activity and increased fat mass as well as the metabolic syndrome [2Bedogni G. Miglioli L. Masutti F. Tiribelli C. Marchesini G. Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study.Hepatology. 2005; 42: 44-52Crossref PubMed Scopus (1037) Google Scholar, 3Vilar-Gomez E. Martinez-Perez Y. Calzadilla-Bertot L. Torres-Gonzalez A. Gra-Oramas B. Gonzalez-Fabian L. et al.Weight Loss via Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis.Gastroenterology. 2015; ([Epub ahead of print])https://doi.org/10.1053/j.gastro.2015.04.005Abstract Full Text Full Text PDF PubMed Scopus (1229) Google Scholar]. The first observation that a reduction in muscle tissue (better known as sarcopenia) could be involved in NAFLD came from the Korean Sarcopenic Obesity Study [[4]Hong H.C. Hwang S.Y. Choi H.Y. Yoo H.J. Seo J.A. Kim S.G. et al.Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study.Hepatology. 2014; 59: 1772-1778Crossref PubMed Scopus (278) Google Scholar]. The authors found that individuals with age-related sarcopenia which was associated with higher body mass index (BMI) and fat mass had an increased prevalence of NAFLD. By analyzing the same database, previous studies had shown that, during aging, the increase in fat mass and the decrease in muscle mass resulted in an increase in metabolic disorders [[5]Lim S. Kim J.H. Yoon J.W. Kang S.M. Choi S.H. Park Y.J. et al.Sarcopenic obesity: prevalence and association with metabolic syndrome in the Korean Longitudinal Study on Health and Aging (KLoSHA).Diabetes Care. 2010; 33: 1652-1654Crossref PubMed Scopus (387) Google Scholar]. Type 2 diabetes has also been found to be independently associated with sarcopenia [[6]Kim T.N. Park M.S. Yang S.J. Yoo H.J. Kang H.J. Song W. et al.Prevalence and determinant factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study (KSOS).Diabetes Care. 2010; 33: 1497-1499Crossref PubMed Scopus (399) Google Scholar]. These studies have led to the hypothesis that leptin and other adipocytokines from the adipose tissue increase muscle catabolism and consequent sarcopenia and reduced physical activity which, through a vicious cycle, results in increased fat accumulation and weight gain. In this issue of Journal of Hepatology, Lee and coworkers [[7]Lee Y.H. Jung K.S. Kim S.U. Yoon H.J. Yun Y.J. Lee B.W. et al.Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: nationwide surveys (KNHANES 2008–2011).J Hepatol. 2015; 63: 486-493Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar] provide further information on the relationship between sarcopenia and NAFLD by analyzing the data from the Korea National Health and Nutrition Examination Survey. The opportunity to derive data from this large population study was based on the application of non-invasive scores, with an acceptable positive predictive index, for the diagnosis of NAFLD. Dual-energy X-ray absorptiometry was used for the assessment of body composition to define changes in muscle mass. Sarcopenia was diagnosed using the skeletal muscle index (SMI) and defined as <1 standard deviation below the average of a young reference population. The key finding of this study was the strong association between sarcopenia and NAFLD regardless of obesity or metabolic syndrome. Both non-obese and obese subjects showed a significantly increased prevalence of NAFLD when sarcopenia was present (non-obese non–sarcopenic: 4–14% vs. non–obese sarcopenic: 9–30%; p <0.001, and obese non–sarcopenic 50–72% vs. obese sarcopenic 61–83%; p <0.001). Similar results were found when patients were stratified by the presence or absence of metabolic syndrome. Interestingly, the authors also examined the impact of regular exercise in patients with NAFLD and found that in obese subjects with preserved skeletal muscle mass, regular exercise was associated with a reduced probability of NAFLD (46 vs. 55% p <0.001). Furthermore, among patients with NAFLD, the presence of sarcopenia was also independently associated with a higher probability of advanced liver fibrosis (evaluated through fibrosis predictors). It is important to note that in the study by Lee, diagnosis of sarcopenia was made using the SMI, a ratio of the appendicular skeletal muscle (ASM) and body weight (BW). SMI may decrease when the fat mass is enhanced, either for obesity or for aging, due to the increase in body mass and therefore the absolute decrease in muscle tissue may be lower than indicated [[8]Kim S.W. Jung H.W. Which one is associated with nonalcoholic fatty liver disease? Small muscle mass or large fat mass.Hepatology. 2015; 61: 1764Crossref PubMed Scopus (5) Google Scholar]. Recently however, in a more limited group of patients, sarcopenia evaluated using computed tomographic (CT) scans, a method which allows precise quantification of muscle mass, was also reported to be associated to the development of NASH or NASH and cirrhosis [9Issa D. Alkhouri N. Tsien C. Shah S. Lopez R. McCullough A. et al.Presence of sarcopenia (muscle wasting) in patients with nonalcoholic steatohepatitis.Hepatology. 2014; 60: 428-429Crossref PubMed Scopus (31) Google Scholar, 10Dasarathy J. Periyalwar P. Allampati S. Bhinder V. Hawkins C. Brandt P. et al.Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease.Liver Int. 2014; 34: e118-e127Crossref PubMed Scopus (92) Google Scholar]. An increasingly recognized limitation of body composition measurements is the difficulty of quantifying muscle mass with precision [11Bredella M.A. Ghomi R.H. Thomas B.J. Torriani M. Brick D.J. Gerweck A.V. et al.Comparison of DXA and CT in the assessment of body composition in premenopausal women with obesity and anorexia nervosa.Obesity (Silver Spring). 2010; 18: 2227-2233Crossref PubMed Scopus (135) Google Scholar, 12Giusto M. Lattanzi B. Albanese C. Galtieri A. Farcomeni A. Giannelli V. et al.Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.Eur J Gastroenterol Hepatol. 2015; 27: 328-334Crossref PubMed Scopus (130) Google Scholar]. A number of methods have been described including DEXA and image analysis using CT or magnetic resonance imaging (MRI). A major limitation of CT and MRI despite their recognized accuracy in identifying skeletal muscle is due to their cost and logistics in population studies. DEXA remains the best option and even though DEXA measures non-fat mass and not muscle mass directly, appendicular non-fat, non-bone mass is predominantly skeletal muscle. Furthermore, the authors acknowledge that muscle mass can be measured using DEXA but the impact on quality of the muscle is not known. This is especially relevant since in type 2 diabetes mellitus, an insulin resistant state, inter- and intra-myocellular fat are increased. Neither muscle function or strength were measured in the study by Lee [[7]Lee Y.H. Jung K.S. Kim S.U. Yoon H.J. Yun Y.J. Lee B.W. et al.Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: nationwide surveys (KNHANES 2008–2011).J Hepatol. 2015; 63: 486-493Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar] and it is not clear if the sarcopenia in patients with NAFLD and metabolic syndrome is associated with reduced muscle strength. Contractile function of the muscle does correlate with outcomes in chronic diseases but whether such an association exists in metabolic dysfunction is not known at this time. To understand if the association between sarcopenia and NAFLD is a cause or a consequence, there is a need to identify the possible pathophysiological mechanism relating muscle, adipose tissue and the liver. Recognition that the skeletal muscle is an endocrine organ secreting various myokines may help to understand its role in the development of fatty liver [[13]Henningsen J. Rigbolt K.T. Blagoev B. Pedersen B.K. Kratchmarova I. Dynamics of the skeletal muscle secretome during myoblast differentiation.Mol Cell Proteomics. 2010; 9: 2482-2496Crossref PubMed Scopus (221) Google Scholar] (Fig. 1). Focusing on the skeletal muscle and on the mediators that link the muscle-liver-adipose tissue axis, is likely to provide a very novel and exciting area for therapeutic development [14McPherron A.C. Guo T. Bond N.D. Gavrilova O. Increasing muscle mass to improve metabolism.Adipocyte. 2013; 2: 92-98Crossref PubMed Google Scholar, 15Dasarathy S. Is the adiponectin-AMPK-mitochondrial axis involved in progression of nonalcoholic fatty liver disease?.Hepatology. 2014; 60: 22-25Crossref PubMed Scopus (23) Google Scholar]. A number of animal studies have shown that myostatin, a TGFβ superfamily member, which was initially discovered as a regulator of skeletal muscle mass, has significant hepatic effects by regulating skeletal muscle metabolism. Blocking myostatin not only increases muscle mass but also protects mice from fatty liver and improves insulin resistance [16Bonala S. McFarlane C. Ang J. Lim R. Lee M. Chua H. et al.Pid1 induces insulin resistance in both human and mouse skeletal muscle during obesity.Mol Endocrinol. 2013; 27: 1518-1535Crossref PubMed Scopus (21) Google Scholar, 17Zhang C. McFarlane C. Lokireddy S. Bonala S. Ge X. Masuda S. et al.Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway.Diabetologia. 2011; 54: 1491-1501Crossref PubMed Scopus (117) Google Scholar]. Furthermore, myostatin also promotes an increase in muscle mass depending on the time of exposure of adipocytes in their development [[18]Dasarathy S. Muc S. Runkana A. Mullen K.D. Kaminsky-Russ K. McCullough A.J. Alteration in body composition in the portacaval anastamosis rat is mediated by increased expression of myostatin.Am J Physiol Gastrointest Liver Physiol. 2011; 301: G731-G738Crossref PubMed Scopus (13) Google Scholar]. Myostatin receptor, Activin IIbr, has been reported, albeit in abstract form only, in hepatic stellate cells. This raises the interesting question of whether fatty liver results in sarcopenia via activation of myostatin in the skeletal muscle, or whether is sarcopenia the primary abnormality mediated by myostatin that functions in an endocrine manner to activate the fibrogenic hepatic stellate cells. Adiponectin is another potential mediator of the adipose tissue muscle axis that alters hepatic metabolism. Adiponectin receptors in the muscle have been reported to regulate insulin signaling and increase fatty acid oxidation but whether there is an adiponectin-myostatin cross-talk has been speculated upon but never proven [[15]Dasarathy S. Is the adiponectin-AMPK-mitochondrial axis involved in progression of nonalcoholic fatty liver disease?.Hepatology. 2014; 60: 22-25Crossref PubMed Scopus (23) Google Scholar]. Obesity and adipose tissue inflammation are accompanied by hypo-adiponectinemia and adiponectin improves insulin signaling. Since myostatin increases adipose tissue mass, and this in turn decreases adiponectin secretion, the liver-muscle-adipose tissue perturbation may actually begin in the skeletal muscle and act on both the liver and adipose tissue. Interleukin-6 is another myokine that potentially regulates hepatic fatty acid oxidation via an AMPK dependent mechanism. Secretory and signaling perturbations of other myokines that regulate lipid and glucose metabolism that include myonectin and irisin have been suggested to contribute to the development of insulin resistance and fatty liver [19Seldin M.M. Peterson J.M. Byerly M.S. Wei Z. Wong G.W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis.J Biol Chem. 2012; 287: 11968-11980Crossref PubMed Scopus (275) Google Scholar, 20Polyzos S.A. Kountouras J. Anastasilakis A.D. Geladari E.V. Mantzoros C.S. Irisin in patients with nonalcoholic fatty liver disease.Metabolism. 2014; 63: 207-217Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar]. In addition to myokines regulating metabolism, skeletal muscle contributes to the resting energy and maximum energy expenditure [[21]Glass C. Hipskind P. Tsien C. Malin S.K. Kasumov T. Shah S.N. et al.Sarcopenia and a physiologically low respiratory quotient in patients with cirrhosis: a prospective controlled study.J Appl Physiol. 1985; 2013: 559-565Google Scholar]. Skeletal muscle mitochondrial dysfunction has been reported with muscle atrophy and whether impaired skeletal muscle substrate and energy utilization contribute to the development and progression of fatty liver is not known. Given the beneficial effects of increased physical activity on both the hepatic and non-hepatic components of the metabolic syndrome, targeting skeletal muscle mitochondrial function is another attractive approach to treat metabolic disorders including NAFLD. The present study adds to the existing literature on sarcopenia and its impact on severity and possibly outcomes in NAFLD. These are exciting translational human data generated from basic biology of the muscle-liver axis that provide a compelling rationale to study the skeletal muscle as a primary therapeutic target in NAFLD and metabolic syndrome. Although the study of Lee and coworkers has limitations, including the absence of histological diagnosis of NAFLD and the use of muscular indices, identifying a strong and direct contribution of the skeletal muscle to hepatic disease is likely to result in a broader therapeutic approach to NAFLD. SD is supported by grants NIH DK83414 and NIH DKUDK 061732. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.