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Published on: October 4, 2024
TAK1 preserves skeletal muscle mass and mitochondrial function through redox homeostasis
Anirban Roy1,2, Aditya K Sharma1,2, Kushal Nellore1
1Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine Louisville KY USA.
Abstract:
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.
Insights
Transforming growth factor-β activated kinase 1 (TAK1) is crucial for maintaining skeletal muscle mass. Disrupting TAK1 causes muscle atrophy by impairing redox signaling, but oxidative stress reduction can restore muscle function.
Area of Science:
- Muscle physiology and molecular signaling
- Redox biology and oxidative stress
- Skeletal muscle atrophy and regeneration
Background:
- Skeletal muscle atrophy is a significant issue in chronic diseases, aging, and disuse.
- Transforming growth factor-β activated kinase 1 (TAK1) is vital for muscle growth and maintenance.
- The precise mechanisms linking TAK1 to muscle mass preservation are not fully understood.
Purpose of the Study:
- To investigate the role of TAK1 in maintaining skeletal muscle mass and function.
- To elucidate the mechanisms by which TAK1 regulates muscle health, focusing on redox signaling.
- To determine if mitigating oxidative stress can counteract TAK1 deficiency-induced muscle atrophy.
Main Methods:
- Generation of inducible skeletal muscle-specific Tak1-knockout mice.
- Assessment of skeletal muscle mass, contractile function, and redox balance.
- Analysis of signaling pathways, including the ubiquitin-proteasome system and autophagy.
- Evaluation of fiber type transition and mitochondrial respiration.
Main Results:
- Targeted ablation of TAK1 in skeletal muscle disrupts redox signaling, leading to reactive oxygen species accumulation, muscle wasting, and loss of contractile function.
- Suppression of oxidative stress with Trolox improved muscle contractile function and inhibited catabolic signaling pathways.
- Trolox treatment also reduced ubiquitin-proteasome system and autophagy markers in TAK1-deficient muscle.
- Inhibition of oxidative stress prevented slow-to-fast fiber type transition and enhanced mitochondrial respiration.
Conclusions:
- TAK1 is essential for maintaining skeletal muscle mass and health by regulating redox homeostasis.
- Oxidative stress plays a critical role in TAK1 deficiency-induced muscle atrophy.
- Targeting oxidative stress pathways presents a potential therapeutic strategy for combating muscle wasting conditions associated with TAK1 dysfunction.
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