# TAK1 signaling in skeletal muscle

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2021 · $429,734

## Abstract

Abstract
Loss of skeletal muscle mass is a devastating complication of a wide range of diseases and
conditions. However, there is still no approved therapy to prevent muscle wasting partly because the
mechanisms that regulate skeletal muscle mass remain enigmatic. Accumulating evidence suggests
that an array of signaling pathways regulates skeletal muscle mass mainly through modulating the
rate of protein synthesis and degradation. However, upstream signaling mechanisms that are involved
in the regulation of muscle mass remain poorly understood. During the current funding of this project,
we showed TRAF6 mediates muscle atrophy and inhibits muscle regeneration in a variety of catabolic
conditions. We also demonstrated that TRAF6 and TAK1 are important regulators of satellite cell
homeostasis in adult skeletal muscle. In contrast to TRAF6, of which activation, causes muscle
wasting, we have discovered that TAK1 is essential for skeletal muscle growth and maintenance of
muscle mass in adults. Inducible myofiber-specific inactivation of TAK1 in mice (henceforth TAK1mko)
leads to severe muscle wasting and development of kyphosis. The positive role of TAK1 in muscle
growth is also supported by our findings that the activation of TAK1 is dramatically increased in
skeletal muscle undergoing hypertrophy. Our experiments also suggest that TAK1 is required for the
activation of specific intracellular pathways which promote skeletal muscle growth. Moreover, our
studies indicate that TAK1 may be required for the activation of autophagy/mitophagy, regulation of
mitochondrial structure and function, and maintenance of redox balance in skeletal muscle of adults.
Based on our preliminary data, we hypothesize that (I) TAK1 promotes skeletal muscle growth and
inhibits atrophy through augmenting protein synthesis and preventing oxidative stress; (II) TAK1
induces the activation of specific intracellular signaling pathways to augment skeletal muscle mass;
and (III) TAK1 is required for the activation of autophagy/mitophagy and regulation of mitochondrial
dynamics (i.e. biogenesis, fusion, and fission) and respiratory function in adult skeletal muscle. To test
these hypotheses, in the next phase of the project, we propose to address the following three specific
aims: (1) Establish the role and investigate the molecular mechanisms by which TAK1 promotes
skeletal muscle growth and prevents atrophy; (2) Investigate the signaling mechanisms by which
TAK1 regulates skeletal muscle mass; and (3) Investigate the role of TAK1 in regulation of autophagy
and mitochondrial content and function in adult skeletal muscle.

## Key facts

- **NIH application ID:** 10201515
- **Project number:** 5R01AR059810-11
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** ASHOK KUMAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,734
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201515

## Citation

> US National Institutes of Health, RePORTER application 10201515, TAK1 signaling in skeletal muscle (5R01AR059810-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201515. Licensed CC0.

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