Regulatory circuitry of TWEAK-Fn14 system and PGC-1? in skeletal muscle atrophy program.

ABSTRACT: Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) 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-1? preserves muscle mass in several conditions, including functional denervation and aging. However, it remains unknown whether there is any regulatory interaction between PGC-1? and TWEAK-Fn14 system during muscle atrophy. Here we demonstrate that TWEAK significantly reduces the levels of PGC-1? and mitochondrial content (?50%) in skeletal muscle. Levels of PGC-1? 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-1? inhibited progressive muscle wasting in TWEAK-Tg mice. PGC-1? inhibited the TWEAK-induced activation of NF-?B (?50%) and dramatically reduced (?90%) the expression of atrogenes such as MAFbx and MuRF1. Intriguingly, muscle-specific overexpression of PGC-1? 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-1?. Overexpression of PGC-1? not only blocks the TWEAK-induced atrophy program but also diminishes the expression of Fn14 in denervated skeletal muscle.

SUBMITTER: Hindi SM 

PROVIDER: S-EPMC3929677 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature