PGC-1α over-expression suppresses the skeletal muscle atrophy and myofiber-type composition during hindlimb unloading

Disuse leads to severe muscle atrophy and a slow-to-fast myofiber-type transition. PGC-1α (Peroxisome proliferator-activated receptor <i>γ</i> coactivator 1α) is documented to play an important role in muscle atrophy and slow-twitch myofiber determination. Transcription of atrophy-related Atrogin-1 by FoxO3 can be reduced by PGC-1α. While Smad3 augments FoxO3-induced Atrogin-1 and MuRF1 promoter activity. So PGC-1α, as a transcription co-activator, may regulate hindlimb unloading (HU)-induced myofiber-type transition and muscle atrophy through Smad3. Our results showed that transgenic PGC-1α mice resisted HU-induced muscle loss, atrophy-related genes expression, and slow-to-fast myofiber_-type transition. Furthermore, over-expression of PGC-1α resisted the increase in pSmad3 during muscle atrophy <i>in vivo</i> and <i>in vitro</i>. And, PGC-1α over-expression inhibited the expression of atrogenes via suppressing the phosphorylation of Smad3 <i>in vitro</i>. Thus, PGC-1α is effective in regulating myofiber-type transition during HU, and it alleviates skeletal muscle atrophy partially through suppressing the activation of Smad3. PGC-1α overexpression alleviates HU-induced myofiber-type transition and may attenuate muscle atrophy partially via suppressing pSmad3.

废用可引发严重的肌肉萎缩，并伴随肌纤维类型从慢肌表型向快肌表型的转变。过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α，Peroxisome proliferator-activated receptor γ coactivator 1α）已被证实，在肌肉萎缩及慢肌肌纤维分型调控中发挥关键作用。叉头框O3（FoxO3）介导的萎缩相关基因Atrogin-1的转录可被PGC-1α抑制；而Smad3则可增强FoxO3诱导的Atrogin-1与肌肉环指蛋白1（MuRF1）的启动子活性。因此，作为转录辅激活因子的PGC-1α，或可通过Smad3通路，调控后肢去负荷（HU，hindlimb unloading）诱导的肌纤维类型转变与肌肉萎缩。本研究结果显示，PGC-1α转基因小鼠可抵抗HU诱导的肌肉丢失、萎缩相关基因表达异常上调，以及慢肌向快肌的肌纤维类型转变。进一步实验证实，在体内（in vivo）与体外（in vitro）模型中，PGC-1α过表达均可抑制肌肉萎缩过程中磷酸化Smad3（pSmad3）水平的升高。此外，体外实验表明，PGC-1α过表达可通过抑制Smad3的磷酸化，下调萎缩相关基因的表达。综上，PGC-1α可有效调控HU过程中的肌纤维类型转变，并可通过抑制Smad3的激活，部分缓解骨骼肌萎缩。PGC-1α过表达可减轻HU诱导的肌纤维类型转变，并可通过抑制pSmad3通路，部分改善肌肉萎缩。