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TAK1/TRAF6 signalling in regulation of skeletal muscle mass
Author(s) -
Kumar Ashok,
Hindi Sajedah M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.614.7
Subject(s) - skeletal muscle , microbiology and biotechnology , denervation , muscle hypertrophy , muscle atrophy , signal transduction , endocrinology , biology , protein kinase a , medicine , chemistry , kinase
Loss of skeletal muscle mass is a devastating consequence of a large number of chronic disease states and several other conditions such as starvation, denervation, immobilization, and aging. However, the signaling and molecular mechanisms that regulate skeletal muscle growth and atrophy remain less understood. It is now evident that a complex array of signaling pathways regulates skeletal muscle mass primarily through modulating the rate of protein synthesis and degradation. Transforming growth factor β (TGF‐β) activated kinase 1 (TAK1), a member of the MEK kinase family, is an important signaling protein which activates multiple signaling pathways in response to cytokines, growth factors, and microbial products. In many signaling cascades, TRAF6 ubiquitylates and activates TAK1. We have previously reported that TRAF6 mediates skeletal muscle atrophy in response to denervation, starvation, and cancer growth. We have now investigated the role of TAK1 in the regulation of adult skeletal muscle mass. Our results demonstrate that inducible inactivation of TAK1 leads to severe muscle wasting and development of kyphosis in adult mice. Moreover, denervation‐induced muscle atrophy is exacerbated in skeletal muscle‐specific TAK1 knockout mice. TAK1 is required for the activation of specific intracellular signaling pathways which promote skeletal muscle growth and prevent atrophy. Inactivation of TAK1 inhibits protein synthesis, induces protein degradation, and causes oxidative stress in skeletal muscle of adult mice. We have also found that deletion of TAK1 leads to accumulation of dysfunctional mitochondria in skeletal muscle potentially due to the inhibition of mitophagy. Intriguingly, phosphorylation of TAK1 is dramatically induced in skeletal muscle of mice undergoing load‐induced hypertrophy. Importantly, targeted inactivation of TAK1 blunts skeletal muscle hypertrophy in response to functional overload. Overall, our experiments suggest that TAK1 is a key regulator of skeletal muscle mass. Support or Funding Information National Institute of Health grants AR059810, AR068313, and AG029623