The University of Queensland, Nuclear Receptor and Skeletal Muscle Group, Institute for Molecular Bioscience, Queensland, Australia.
Int J Obes (Lond). 2010 Mar;34(3):524-36. doi: 10.1038/ijo.2009.265. Epub 2009 Dec 22.
The Ski gene regulates skeletal muscle differentiation in vitro and and in vivo. In the c-Ski overexpression mouse model there occurs marked skeletal muscle hypertrophy with decreased adipose tissue mass. In this study, we have investigated the underlying molecular mechanisms responsible for the increased skeletal muscle and decreased adipose tissue mass in the c-Ski mouse.
Growth and body composition analysis (tissue weights and dual energy X-ray absorptiometry) coupled with skeletal muscle and white adipose gene expression and metabolic phenotyping in c-Ski mice and wild-type (WT) littermate controls was performed.
The growth and body composition studies confirmed the early onset of accelerated body growth, with increased lean mass and decreased fat mass in the c-Ski mice. Gene expression analysis in skeletal muscle from c-Ski mice compared with WT mice showed significant differences in myogenic and lipogenic gene expressions that are consistent with the body composition phenotype. Skeletal muscle of c-Ski mice had significantly repressed Smad1, 4, 7 and myostatin gene expression and elevated myogenin, myocyte enhancer factor 2, insulin-like growth factor-1 receptor and insulin-like growth factor-2 expression. Strikingly, expression of the mRNAs encoding the master lipogenic regulators, sterol-regulatory enhancer binding protein 1c (SREBP1c), and the nuclear receptor liver X-receptor-alpha, and their downstream target genes, SCD-1 and FAS, were suppressed in skeletal muscle of c-Ski mice, as were the expressions of other nuclear receptors involved in adipogenesis and metabolism, such as peroxisome proliferator-activated receptor-gamma, glucocorticoid receptor and retinoic acid receptor-related orphan receptor-alpha. Transfection analysis demonstrated Ski repressed the SREBP1c promoter. Moreover, palmitate oxidation and oxidative enzyme activity was increased in skeletal muscle of c-Ski mice. These results suggest that the Ski phenotype involves attenuated lipogenesis, decreased myostatin signalling, coupled to increased myogenesis and fatty acid oxidation.
Ski regulates several genetic programs and signalling pathways that regulate skeletal muscle and adipose mass to influence body composition development, suggesting that Ski may have a role in risk for obesity and metabolic disease.
Ski 基因调控体外和体内的骨骼肌分化。在 c-Ski 过表达小鼠模型中，骨骼肌明显肥大，脂肪组织质量减少。在这项研究中，我们研究了导致 c-Ski 小鼠骨骼肌增加和脂肪组织减少的潜在分子机制。
对 c-Ski 小鼠和野生型（WT）同窝对照小鼠的生长和体成分分析（组织重量和双能 X 射线吸收法），以及骨骼肌和白色脂肪组织基因表达和代谢表型进行了研究。
生长和体成分研究证实，c-Ski 小鼠的体重增长提前开始，表现为瘦体重增加，脂肪体重减少。与 WT 小鼠相比，c-Ski 小鼠骨骼肌的基因表达分析显示，肌生成和脂肪生成基因表达存在显著差异，与体成分表型一致。c-Ski 小鼠的骨骼肌中 Smad1、4、7 和肌肉生长抑制素基因表达明显受到抑制，而肌细胞增强因子 2、胰岛素样生长因子 1 受体和胰岛素样生长因子 2 表达升高。引人注目的是，c-Ski 小鼠骨骼肌中编码主脂质调节因子固醇调节元件结合蛋白 1c（SREBP1c）和核受体肝 X 受体-α及其下游靶基因 SCD-1 和 FAS 的 mRNA 表达受到抑制，参与脂肪生成和代谢的其他核受体，如过氧化物酶体增殖物激活受体-γ、糖皮质激素受体和维甲酸受体相关孤儿受体-α的表达也受到抑制。转染分析表明 Ski 抑制了 SREBP1c 启动子。此外，c-Ski 小鼠骨骼肌中的棕榈酸氧化和氧化酶活性增加。这些结果表明，Ski 表型涉及脂肪生成减少、肌肉生长抑制素信号减弱，同时伴有肌生成和脂肪酸氧化增加。
Ski 调节了几个遗传程序和信号通路，这些通路调节骨骼肌和脂肪量，从而影响身体成分的发育，这表明 Ski 可能在肥胖和代谢疾病的风险中发挥作用。
