2Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 South Preston St., Louisville, KY 40202, USA.
FASEB J. 2014 Mar;28(3):1398-411. doi: 10.1096/fj.13-242123. Epub 2013 Dec 10.
Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and TNF-like weak inducer of apoptosis (TWEAK)-Fn14 system are key regulators of skeletal muscle mass in various catabolic states. While the activation of TWEAK-Fn14 signaling causes muscle wasting, PGC-1α preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1α and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1α and mitochondrial content (∼50%) in skeletal muscle. Levels of PGC-1α are significantly increased in skeletal muscle of TWEAK-knockout (KO) and Fn14-KO mice compared to wild-type mice on denervation. Transgenic (Tg) overexpression of PGC-1α inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1α inhibited the TWEAK-induced activation of NF-κB (∼50%) and dramatically reduced (∼90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1α also prevented the inducible expression of Fn14 in denervated skeletal muscle. Collectively, our study demonstrates that TWEAK induces muscle atrophy through repressing the levels of PGC-1α. Overexpression of PGC-1α not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.
由于缺乏活动导致的骨骼肌减少会对身体功能产生严重的负面影响。越来越多的证据表明，过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）和肿瘤坏死因子样弱凋亡诱导因子（TWEAK）-Fn14 系统是各种分解代谢状态下骨骼肌质量的关键调节因子。虽然 TWEAK-Fn14 信号的激活会导致肌肉减少，但 PGC-1α 在多种情况下（包括功能失神经和衰老）都能维持肌肉质量。然而，目前尚不清楚 PGC-1α 和 TWEAK-Fn14 系统在肌肉萎缩过程中是否存在任何调节相互作用。在这里，我们证明 TWEAK 可显著降低骨骼肌中 PGC-1α 和线粒体含量（约 50%）。与野生型小鼠相比，在去神经支配的情况下，TWEAK 敲除（KO）和 Fn14-KO 小鼠的骨骼肌中 PGC-1α 水平显著增加。PGC-1α 的转基因（Tg）过表达抑制了 TWEAK-Tg 小鼠的进行性肌肉减少。PGC-1α 抑制了 TWEAK 诱导的 NF-κB（约 50%）的激活，并显著降低（约 90%）了肌萎缩基因如 MAFbx 和 MuRF1 的表达。有趣的是，肌肉特异性过表达 PGC-1α 也可防止去神经支配的骨骼肌中 Fn14 的诱导表达。总的来说，我们的研究表明，TWEAK 通过抑制 PGC-1α 的水平来诱导肌肉萎缩。PGC-1α 的过表达不仅阻断了 TWEAK 诱导的萎缩程序，还降低了去神经支配的骨骼肌中 Fn14 的表达。
