| First Author | Hindi SM | Year | 2014 |
| Journal | FASEB J | Volume | 28 |
| Issue | 3 | Pages | 1398-411 |
| PubMed ID | 24327607 | Mgi Jnum | J:210689 |
| Mgi Id | MGI:5571667 | Doi | 10.1096/fj.13-242123 |
| Citation | Hindi SM, et al. (2014) Regulatory circuitry of TWEAK-Fn14 system and PGC-1alpha in skeletal muscle atrophy program. FASEB J 28(3):1398-411 |
| abstractText | Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) 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-1alpha preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1alpha and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1alpha and mitochondrial content ( approximately 50%) in skeletal muscle. Levels of PGC-1alpha 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-1alpha inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1alpha inhibited the TWEAK-induced activation of NF-kappaB ( approximately 50%) and dramatically reduced ( approximately 90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1alpha 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-1alpha. Overexpression of PGC-1alpha not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle. |
