title: Regulatory circuitry of TWEAK-Fn14 system and PGC-1α 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 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.
authors: 2Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 South Preston St., Louisville, KY 40202, USA. ashok.kumar@louisville.edu.
authors: Sajedah M
authors: SM
authors: Hindi
authors: Vivek
authors: V
authors: Mishra
authors: Shephali
authors: S
authors: Bhatnagar
authors: Marjan M
authors: MM
authors: Tajrishi
authors: Yuji
authors: Y
authors: Ogura
authors: Zhen
authors: Z
authors: Yan
authors: Linda C
authors: LC
authors: Burkly
authors: Timothy S
authors: TS
authors: Zheng
authors: Ashok
authors: A
authors: Kumar
mesh_terms: D000818:Animals; D000074049:Cytokine TWEAK; D024202:Electrophoretic Mobility Shift Assay; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000473:pathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D000074050:TWEAK Receptor; D014157:Transcription Factors / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D000074049:Cytokine TWEAK; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D014157:Transcription Factors; D048069:Tumor Necrosis Factors
keywords: MAFBx; MuRF1; NF-κB; SP-1; denervation; mitochondria; ubiquitin-proteasome system