Serum Myostatin is Upregulated in Obesity and Correlates with Insulin Resistance in Humans

Abstract

Obesity and type 2 diabetes mellitus have reached an epidemic level, thus novel treatment concepts need to be identified. Myostatin, a myokine known for restraining skeletal muscle growth, has been associated with the development of insulin resistance and type 2 diabetes mellitus. Yet, little is known about the regulation of myostatin in human obesity and insulin resistance. We aimed to investigate the regulation of myostatin in obesity and uncover potential associations between myostatin, metabolic markers and insulin resistance/sensitivity indices. Circulating active myostatin concentration was measured in the serum of twenty-eight severely obese non-diabetic patients compared to a sex and age matched lean and overweight control group (n=22). Insulin resistance/sensitivity was assessed in the obese group. Skeletal muscle and adipose tissue specimens from the obese group were collected during elective bariatric surgery. Adipose tissue samples from lean and overweight subjects were collected during elective abdominal surgery. Myostatin concentration was increased in obese compared to lean individuals, while myostatin adipose tissue expression did not differ. Muscle myostatin gene expression strongly correlated with expression of metabolic genes such as IRS1, PGC1α, SREBF1. Circulating myostatin concentration correlated positively with insulin resistance indices and negatively with insulin sensitivity indices. The best correlation was obtained for the oral glucose insulin sensitivity index. Our results point to an interesting correlation between myostatin and insulin resistance/sensitivity in humans, and emphasize its need for further evaluation as a pharmacological target in the prevention and treatment of obesity-associated metabolic complications.

Key words

obesity - type 2 diabetes mellitus - insulin resistance/sensitivity indices

^* Equal contributors

• References

• 1 McFarlane C, Langley B, Thomas M. et al. Proteolytic processing of myostatin is auto-regulated during myogenesis. Dev Biol 2005; 283: 58-69
• 2 Huang Z, Chen X, Chen D. Myostatin: A novel insight into its role in metabolism, signal pathways, and expression regulation. Cell Signal 2011; 23: 1441-1446
• 3 McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997; 387: 83-90
• 4 Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A 2001; 98: 9306-9311
• 5 Lin J, Arnold HB, Della-Fera MA. et al. Myostatin knockout in mice increases myogenesis and decreases adipogenesis. Biochem Biophys Res Commun 2002; 291: 701-706
• 6 McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002; 109: 595-601
• 7 Wilkes JJ, Lloyd DJ, Gekakis N. Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance. Diabetes 2009; 58: 1133-1143
• 8 Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem Biophys Res Commun 2005; 337: 248-255
• 9 Guo T, Jou W, Chanturiya T. et al. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PloS one 2009; 4: e4937
• 10 Dong J, Dong Y, Dong Y. et al. Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Int J Obes (Lond) 2016; 40: 434-442
• 11 Dobbs R, Sawers C, Thompson F. et al. Overcoming obesity: An initial economic analysis. McKinsey Global Institute; 2014
• 12 Kelly T, Yang W, Chen CS. et al. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 2008; 32: 1431-1437
• 13 Hittel DS, Berggren JR, Shearer J. et al. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 2009; 58: 30-38
• 14 Hittel DS, Axelson M, Sarna N. et al. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc 2010; 42: 2023-2029
• 15 Itariu BK, Zeyda M, Hochbrugger EE. et al. Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: A randomized controlled trial. Am J Clin Nutr 2012; 96: 1137-1149
• 16 Leitner L, Schuch K, Jurets A. et al. Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase-cleaved osteopontin in obesity. Obesity (Silver Spring) 2015; 23: 779-785
• 17 Hanson RL, Pratley RE, Bogardus C. et al. Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 2000; 151: 190-198
• 18 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462-1470
• 19 Patarrão RS, Lautt WW, Macedo MP. Assessment of methods and indexes of insulin sensitivity. Revista Portuguesa de Endocrinologia, Diabetes e Metabolismo 2014; 9: 65-73
• 20 Mari A, Pacini G, Murphy E. et al. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 2001; 24: 539-548
• 21 Bustin SA, Benes V, Garson JA. et al. The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55: 611-622
• 22 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
• 23 Park SE, Park CY, Sweeney G. Biomarkers of insulin sensitivity and insulin resistance: Past, present and future. Crit Rev Clin Lab Sci 2015; 52: 180-190
• 24 Allen DL, Hittel DS, McPherron AC. Expression and function of myostatin in obesity, diabetes, and exercise adaptation. Med Sci Sports Exerc 2011; 43: 1828-1835
• 25 Zhang C, McFarlane C, Lokireddy S. et al. Erratum to: 'Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice' and 'Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway'. Diabetologia 2015; 58: 643
• 26 Lebrasseur NK. Building muscle, browning fat and preventing obesity by inhibiting myostatin. Diabetologia 2012; 55: 13-17
• 27 Allen DL, Cleary AS, Speaker KJ. et al. Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Endocrinol Metab 2008; 294: E918-E927
• 28 Wagner KR, Liu X, Chang X. et al. Muscle regeneration in the prolonged absence of myostatin. Proc Natl Acad Sci U S A 2005; 102: 2519-2524
• 29 McCroskery S, Thomas M, Platt L. et al. Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice. J Cell Sci 2005; 118: 3531-3541
• 30 Kirk S, Oldham J, Kambadur R. et al. Myostatin regulation during skeletal muscle regeneration. J Cell Physiol 2000; 184: 356-363
• 31 Haidet AM, Rizo L, Handy C. et al. Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad Sci U S A 2008; 105: 4318-4322
• 32 Bogdanovich S, Krag TO, Barton ER. et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature 2002; 420: 418-421
• 33 Bernardo BL, Wachtmann TS, Cosgrove PG. et al. Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice. PloS one 2010; 5: e11307
• 34 Zhang C, McFarlane C, Lokireddy S. et al. Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway. Diabetologia 2011; 54: 1491-1501
• 35 Dessalle K, Euthine V, Chanon S. et al. SREBP-1 transcription factors regulate skeletal muscle cell size by controlling protein synthesis through myogenic regulatory factors. PloS one 2012; 7: e50878
• 36 Mouisel E, Relizani K, Mille-Hamard L. et al. Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2014; 307: R444-R454
• 37 Albrecht E, Norheim F, Thiede B. et al. Irisin – a myth rather than an exercise-inducible myokine. Sci Rep 2015; 5: 8889
• 38 Jedrychowski MP, Wrann CD, Paulo JA. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab 2015; 22: 734-740
• 39 Raschke S, Elsen M, Gassenhuber H. et al. Evidence against a beneficial effect of irisin in humans. PloS one 2013; 8: e73680