TNF‐related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle‐wasting cytokine

Abstract

TWEAK cytokine has been implicated in several biological responses including inflammation, angiogenesis, and osteoclastogenesis. We have investigated the role of TWEAK in regulating skeletal muscle mass. Addition of soluble TWEAK protein to cultured myotubes reduced the mean myotube diameter and enhanced the degradation of specific muscle proteins such as CK and MyHCf. The effect of TWEAK on degradation of MyHCf was stronger than its structural homologue, TNF-alpha. TWEAK increased the ubiquitination of MyHCf and the transcript levels of atrogin-1 and MuRF1 ubiquitin ligases. TWEAK inhibited phosphorylation of Akt kinase and its downstream targets GSK-3beta, FOXO1, mTOR, and p70S6K. Furthermore, TWEAK increased the activation of NF-kappaB transcription factor in myotubes. Adenoviral-mediated overexpression of IkappaB alpha deltaN (a degradation-resistant mutant of NF-kappaB inhibitory protein IkappaB alpha) in myotubes blocked the TWEAK-induced degradation of MyHCf. Chronic administration of TWEAK in mice resulted in reduced body and skeletal muscle weight with an associated increase in the activity of ubiquitin-proteasome system and NF-kappaB. Finally, muscle-specific transgenic overexpression of TWEAK decreased the body and skeletal muscle weight in mice. Collectively, our data suggest that TWEAK induces skeletal muscle atrophy through inhibition of the PI3K/Akt signaling pathway and activation of the ubiquitin-proteasome and NF-kappaB systems.

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

“…Nevertheless, it appears that the TWEAK-Fn14 system is active in processes related to growth and remodeling of tissue and organs during development and tissue repair. In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6,7), regulation of muscle development and muscle regeneration (8)(9)(10)(11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus erythematosus-related nephritis (13), 2,4,6-trinitrobenzene sulfonic acid-induced colitis (14), renal and cerebral ischemia (15)(16)(17)(18), and collagen-induced arthritis (19,20).…”

DNA Methyltransferase 3a and Mitogen-activated Protein Kinase Signaling Regulate the Expression of Fibroblast Growth Factor-inducible 14 (Fn14) during Denervation-induced Skeletal Muscle Atrophy

“…It is also notable that Fn14 is expressed at high levels in developing skeletal muscle of neonatal/young mice. However, Fn14 levels are dramatically reduced in skeletal muscle of adult mice (9). Although it is possible that growth factors play a role in the expression of Fn14 in skeletal muscle during development, they are not the key regulators of Fn14 expression in denervated muscle of adult mice because the expression of some of these factors (e.g.…”

“…Adult skeletal muscle expresses minimal levels of Fn14 in unchallenged conditions (8,9). Although the expression of TWEAK does not change significantly, loss of nerve supply causes a rapid and robust increase in the expression of Fn14 in skeletal muscle (8).…”

Tumor Necrosis Factor-related Weak Inducer of Apoptosis Augments Matrix Metalloproteinase 9 (MMP-9) Production in Skeletal Muscle through the Activation of Nuclear Factor-κB-inducing Kinase and p38 Mitogen-activated Protein Kinase

“…We have recently reported that tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK), a proinflammatory cytokine belonging to the TNF superfamily, is a potent skeletal muscle-wasting cytokine (13). Although the exact mechanisms of action of TWEAK in skeletal muscle remain unknown, TWEAK has been found to inhibit the differentiation of myoblasts into myotubes (14).…”

“…Although the exact mechanisms of action of TWEAK in skeletal muscle remain unknown, TWEAK has been found to inhibit the differentiation of myoblasts into myotubes (14). TWEAK also augments the degradation of specific muscle proteins such as MyoD and myosin heavy chain fast type in cultured muscle cells (13,15). Furthermore TWEAK-induced muscle atrophy in vivo is accompanied with significant extracellular matrix abnormalities (13).…”