PGC-1α is important for maintaining the balance of muscle mass and myofiber types in unloaded muscle atrophy

PGC-1α, a transcriptional co-activator, has been shown mainly to determine the development of oxidative myofibers in skeletal muscle. However, whether PGC-1α functions to regulate the unloaded muscle atrophy and composition of myofiber types keeps unclear. MCK-PGC-1α overexpression transgenic mice (TG) and its wild type littermates (WT) were subjected to hindlimb unloading (HU) and induced unloaded muscle atrophy. After 14 days of HU, the mass of gastrocnemius, soleus, and plantaris muscles in WT mice decreased 17.9%, 28.2%, and 14.8%, respectively (P<0.01), compared with ground weight-bearing control muscles. PGC-1α transgenic mice showed a 14.0% (P<0.05), 20.4% (P<0.01), 11.8% decrease in gastrocnemius, soleus, and plantaris muscles mass after HU. To further confirm the effect of PGC-1α over-expression on the muscle mass loss under HU, change rate of muscle-body weight ratio was calculated, and the results indicated that the reduction of change rate of muscle-body weight ratio in PGC-1α transgenic gastrocnemius and soleus was significantly less than in WT mice (P<0.01). Moreover, in TG mice compared to WT mice there were significantly less reduction rate of slow-twitch myofiber MHC-I and MHC-IIa (MHC-I, -3.0±0.2% vs -14.9±4.2%, p<0.01, MHC-IIa, -3.5±2.7% vs -6.2±3.7%, p<0.01 ), while there was significantly less induction rate of fast-twitch myofiber MHC-IIb (MHC-IIb, +0.6±0.6% vs +3.7±2.9%, p<0.01 ). The real-time PCR and Western blot analysis confirmed that PGC-1α overexpression mice markedly rescued the muscle atrophy and myofiber switching from oxidative to glycolytic associated with a decrease in pSmad3 level after 14 days of HU. Importantly, overexpression of PGC-1α in C2C12 myoblasts protected PGC-1α-transfected myotubes from atrophy in vitro and the effect could be partially blocked by inducing pSmad3 with constitutively activated Smad3(C.A. smad3) transfection. Therefore, this study demonstrated a novel role and mechanism for PGC-1α in maintaining the balance of muscle mass and myofiber type MHCs in unloaded muscle atrophy via suppressing Smad3 activation. This report may prompt a hopeful therapeutic strategy for maintaining muscle mass and fiber type composition in disused muscle atrophies such as space weightlessness- or immobilization-induced muscle atrophy. Acknowledgments This work was supported by the Natural Sciences Foundation of China (31171144, 81272177 and 31171148), the State Key Laboratory Grant of Space Medicine Fundamentals and Application (SMFA13A01), and the National Key Laboratory Grant of Human Factors Engineering (SYFD140051801).