TAK1 preserves skeletal muscle mass and mitochondrial function through redox homeostasis

Skeletal muscle atrophy is debilitating consequence of a large number of chronic disease states, aging, and disuse conditions. Skeletal muscle mass is regulated through coordinated activation of a number of signaling cascades. Transforming growth factor-β activated kinase 1 (TAK1) is a central kinase that mediates the activation of multiple signaling pathways in response to various growth factors, cytokines, and microbial products. Accumulating evidence suggests that TAK1 promotes skeletal muscle growth and essential for the maintenance of muscle mass in adults. Targeted inactivation of TAK1 leads to severe muscle wasting and kyphosis in mice. However, the mechanisms by which TAK1 prevents loss of muscle mass remain poorly understood. Through generation of inducible skeletal muscle-specific Tak1-knockout mice, we demonstrate that targeted ablation of TAK1 disrupts redox signaling leading to the accumulation of reactive oxygen species and loss of skeletal muscle mass and contractile function. Suppression of oxidative stress using Trolox improves muscle contractile function and inhibits the activation of catabolic signaling pathways in Tak1-deficient muscle. Moreover, Trolox inhibits the activation of ubiquitin-proteasome system and autophagy markers in skeletal muscle of Tak1-deficient mice. Furthermore, inhibition of oxidative stress using Trolox prevents the slow-to-fast type fiber transition and improves mitochondrial respiration in skeletal muscle of Tak1-deficient mice. Overall, our results demonstrate that TAK1 maintains skeletal muscle mass and health through redox homeostasis.