MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
Sport and Health Sciences, University of Exeter, Exeter, UK.
Geroscience. 2024 Apr;46(2):2033-2049. doi: 10.1007/s11357-023-00956-6. Epub 2023 Oct 6.
Myostatin negatively regulates skeletal muscle growth and appears upregulated in human obesity and associated with insulin resistance. However, observations are confounded by ageing, and the mechanisms responsible are unknown. The aim of this study was to delineate between the effects of excess adiposity, insulin resistance and ageing on myostatin mRNA expression in human skeletal muscle and to investigate causative factors using in vitro models. An in vivo cross-sectional analysis of human skeletal muscle was undertaken to isolate effects of excess adiposity and ageing per se on myostatin expression. In vitro studies employed human primary myotubes to investigate the potential involvement of cross-talk between subcutaneous adipose tissue (SAT) and skeletal muscle, and lipid-induced insulin resistance. Skeletal muscle myostatin mRNA expression was greater in aged adults with excess adiposity than age-matched adults with normal adiposity (2.0-fold higher; P < 0.05) and occurred concurrently with altered expression of genes involved in the maintenance of muscle mass but did not differ between younger and aged adults with normal adiposity. Neither chronic exposure to obese SAT secretome nor acute elevation of fatty acid availability (which induced insulin resistance) replicated the obesity-mediated upregulation of myostatin mRNA expression in vitro. In conclusion, skeletal muscle myostatin mRNA expression is uniquely upregulated in aged adults with excess adiposity and insulin resistance but not by ageing alone. This does not appear to be mediated by the SAT secretome or by lipid-induced insulin resistance. Thus, factors intrinsic to skeletal muscle may be responsible for the obesity-mediated upregulation of myostatin, and future work to establish causality is required.
肌肉生长抑制素负向调节骨骼肌生长，在人类肥胖症中上调，并与胰岛素抵抗相关。然而，这些观察结果受到年龄的影响，其相关机制尚不清楚。本研究旨在区分肥胖、胰岛素抵抗和衰老对人体骨骼肌中肌肉生长抑制素 mRNA 表达的影响，并使用体外模型研究其因果因素。对人体骨骼肌进行了一项横断面的体内研究，以单独分离肥胖和衰老对肌肉生长抑制素表达的影响。体外研究采用人原代肌管，研究皮下脂肪组织（SAT）和骨骼肌之间的潜在串扰以及脂质诱导的胰岛素抵抗对肌肉生长抑制素的潜在影响。与年龄匹配的正常体脂成年人相比，肥胖且年龄较大的成年人的骨骼肌肌肉生长抑制素 mRNA 表达更高（高出 2 倍；P<0.05），并且与参与维持肌肉量的基因的表达改变同时发生，但与正常体脂的年轻和老年成年人之间没有差异。慢性暴露于肥胖的 SAT 分泌组或急性增加脂肪酸可利用性（诱导胰岛素抵抗）均不能在体外复制肥胖介导的肌肉生长抑制素 mRNA 表达的上调。总之，骨骼肌肌肉生长抑制素 mRNA 表达仅在肥胖且胰岛素抵抗的成年老年人中上调，而不是单独由衰老引起。这似乎不是由 SAT 分泌组或脂质诱导的胰岛素抵抗介导的。因此，可能是骨骼肌内在因素导致了肥胖介导的肌肉生长抑制素的上调，需要进一步的因果关系研究。
