Table_3_PGC-1α and PGC-1β Increase Protein Synthesis via ERRα in C2C12 Myotubes.XLSX

The transcriptional coactivators peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and PGC-1β are positive regulators of skeletal muscle mass and energy metabolism; however, whether they influence muscle growth and metabolic adaptations via increased protein synthesis is not clear. This study revealed PGC-1α or PGC-1β overexpression in C2C12 myotubes increased protein synthesis and myotube diameter under basal conditions and attenuated the loss in protein synthesis following the treatment with the catabolic agent, dexamethasone. To investigate whether PGC-1α or PGC-1β signal through the Akt/mTOR pathway to increase protein synthesis, treatment with the PI3K and mTOR inhibitors, LY294002 and rapamycin, respectively, was undertaken but found unable to block PGC-1α or PGC-1β’s promotion of protein synthesis. Furthermore, PGC-1α and PGC-1β decreased phosphorylation of Akt and the Akt/mTOR substrate, p70S6K. In contrast to Akt/mTOR inhibition, the suppression of ERRα, a major effector of PGC-1α and PGC-1β activity, attenuated the increase in protein synthesis and myotube diameter in the presence of PGC-1α or PGC-1β overexpression. To characterize further the biological processes occurring, gene set enrichment analysis of genes commonly regulated by both PGC-1α and PGC-1β was performed following a microarray screen. Genes were found enriched in metabolic and mitochondrial oxidative processes, in addition to protein translation and muscle development categories. This suggests concurrent responses involving both increased metabolism and myotube protein synthesis. Finally, based on their known function or unbiased identification through statistical selection, two sets of genes were investigated in a human exercise model of stimulated protein synthesis to characterize further the genes influenced by PGC-1α and PGC-1β during physiological adaptive changes in skeletal muscle.

转录共激活因子过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC-1α）与PGC-1β是调节骨骼肌质量和能量代谢的积极因子；然而，它们是否通过增加蛋白质合成来影响肌肉生长和代谢适应尚不明确。本研究揭示，在C2C12肌管中PGC-1α或PGC-1β的过表达在基础条件下增加了蛋白质合成和肌管直径，并减轻了在代谢分解剂地塞米松处理后的蛋白质合成减少。为了研究PGC-1α或PGC-1β是否通过Akt/mTOR信号通路增加蛋白质合成，进行了分别使用PI3K和mTOR抑制剂LY294002和雷帕霉素的治疗，但发现无法阻断PGC-1α或PGC-1β对蛋白质合成的促进作用。此外，PGC-1α和PGC-1β降低了Akt及其底物p70S6K的磷酸化。与Akt/mTOR抑制相反，PGC-1α和PGC-1β的主要效应因子ERRα的抑制减轻了PGC-1α或PGC-1β过表达时的蛋白质合成和肌管直径的增加。为进一步描述发生的生物学过程，对受PGC-1α和PGC-1β共同调控的基因集进行了基因集富集分析，这些基因在代谢、线粒体氧化、蛋白质翻译和肌肉发育等类别中富集。这表明同时涉及代谢增加和肌管蛋白质合成的协同反应。最后，基于它们已知的功能或通过统计学选择的无偏识别，在刺激蛋白质合成的临床运动模型中研究了两组基因，以进一步描述PGC-1α和PGC-1β在骨骼肌生理适应性变化中影响的基因。