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- Title
Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program.
- Authors
Hindi, Sajedah M.; Mishra, Vivek; Bhatnagar, Shephali; Tajris, Marjan M.; Yuji Ogura; Zhen Yan; Burkly, Linda C.; Zheng, Timothy S.; Kumar, Ashok
- Abstract
Skeletal muscle wasting attributed to inactivity has significant adverse functional consequences. Accumulating evidence suggests that peroxisome proliferator-activated receptor γ coactivator lot (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.
- Subjects
SKELETAL muscle; PEROXISOME proliferator-activated receptors; APOPTOSIS; MUSCULAR atrophy; DENERVATION
- Publication
FASEB Journal, 2014, Vol 28, Issue 3, p1398
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-242123