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.

The TWEAK–Fn14 dyad is involved in age-associated pathological changes in skeletal muscle

“…In this study, we have investigated whether TWEAK-Fn14 axis has a role in regulation of skeletal muscle mass during aging. Consistent with publised reports that skeletal muscle of adult mice express minimial to undetactable levels of Fn14 [16,27], we did not find any histological or biochemical differences in skeletal muscle of 3-month old WT and Fn14-KO mice. However, the expression of Fn14 is signficantly increased in skeletal muscle with advancing age and the differences in fiber size and biochemical changes became evident in skeletal muscle of WT and Fn14-KO mice at the age of 18 months.…”

Cytokine Signaling in Skeletal Muscle Wasting

“…Recently, TWEAK has been identified as a key mediator of wasting in denervation [18] and cancer [19]. TWEAK induces muscle RING-finger protein 1 (MuRF1) expression via NF-kB activation [10] (Box 2).…”

Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury

“…Therefore, our studies are underway to determine the potential role of heightened muscle inflammation in metabolic disturbances among individuals with SCI. Higher TWEAK R in SCI muscle may also cause impaired oxidative metabolism, as recent animal studies (18,36) have demonstrated that TWEAK inhibits skeletal muscle oxidative metabolism via activating the NF-B signaling pathway, which represses PGC-1␣ levels in skeletal muscle. For example, TWEAK KO mice present with higher skeletal muscle mitochondrial content and oxidative phosphorylation capacity via increasing PGC-1␣ levels compared with wild-type mice.…”