TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine.
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.
Dogra
Charu
C
Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Administration Medical Center, Loma Linda, CA 92357, USA.
Changotra
Harish
H
Wedhas
Nia
N
Qin
Xuezhong
X
Wergedal
Jon E
JE
Kumar
Ashok
A
D000818:Animals; D001835:Body Weight; D000074049:Cytokine TWEAK; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D000074049:Cytokine TWEAK; D009124:Muscle Proteins; D016328:NF-kappa B; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D025801:Ubiquitin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex