Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
TAK1 regulates skeletal muscle mass and mitochondrial function
Sajedah M. Hindi, Shuichi Sato, Guangyan Xiong, Kyle R. Bohnert, Andrew A. Gibb, Yann S. Gallot, Joseph D. McMillan, Bradford G. Hill, Shizuka Uchida, Ashok Kumar
Sajedah M. Hindi, Shuichi Sato, Guangyan Xiong, Kyle R. Bohnert, Andrew A. Gibb, Yann S. Gallot, Joseph D. McMillan, Bradford G. Hill, Shizuka Uchida, Ashok Kumar
View: Text | PDF
Research Article Metabolism Muscle biology

TAK1 regulates skeletal muscle mass and mitochondrial function

  • Text
  • PDF
Abstract

Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-β–activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy. Phosphorylation and enzymatic activity of AMPK are increased, whereas levels of phosphorylated mTOR and p38 MAPK are diminished upon inducible inactivation of TAK1 in skeletal muscle. In addition, targeted inactivation of TAK1 leads to the accumulation of dysfunctional mitochondria and oxidative stress in skeletal muscle of adult mice. Inhibition of TAK1 does not attenuate denervation-induced muscle wasting in adult mice. Finally, TAK1 activity is highly upregulated during overload-induced skeletal muscle growth, and inactivation of TAK1 prevents myofiber hypertrophy in response to functional overload. Overall, our study demonstrates that TAK1 is a key regulator of skeletal muscle mass and oxidative metabolism.

Authors

Sajedah M. Hindi, Shuichi Sato, Guangyan Xiong, Kyle R. Bohnert, Andrew A. Gibb, Yann S. Gallot, Joseph D. McMillan, Bradford G. Hill, Shizuka Uchida, Ashok Kumar

×

Figure 3

Inactivation of TAK1 perturbs the rate of protein synthesis and protein degradation in skeletal muscle.

Options: View larger image (or click on image) Download as PowerPoint
Inactivation of TAK1 perturbs the rate of protein synthesis and protein ...
Six-week-old Tak1fl/fl and Tak1mKO mice were given i.p. injections of tamoxifen, and 3 weeks later, skeletal muscle were collected and processed for biochemical analysis. (A) Immunoblots demonstrating the protein levels of MyHC fast-type, tropomyosin, troponin, sarcomeric α-actin, dystrophin, and unrelated protein GAPDH in GA muscle of Tak1fl/fl and Tak1mKO mice. Dystrophin was run on a separate gel with loading control GAPDH. (B) Densitometry quantification of relative protein levels of MyHC fast-type, tropomyosin, troponin, sarcomeric α-actin, and dystrophin in GA muscle of Tak1fl/fl and Tak1mKO mice. (C) Relative mRNA levels of Myh4 in GA muscle of Tak1fl/fl and Tak1mKO mice assayed by qPCR. (D) Tak1fl/fl and Tak1mKO mice were given i.p. injections of puromycin (0.04 μmol/g body weight). The mice were euthanized 30 minutes later, and GA muscle was collected and processed by Western blot. Immunoblots of puromycin-tagged protein and unrelated protein GAPDH in GA muscle of Tak1fl/fl and Tak1mKO mice. (E) Densitometry quantification of relative levels of puromycin-tagged proteins in GA muscle of Tak1fl/fl and Tak1mKO mice. (F) Fold change in 20S proteasome activity in GA muscle of Tak1fl/fl and Tak1mKO mice measured using a commercially available kit (Catalog # K245, BioVision). (G) Immunoblots showing relative amounts of ubiquitin-conjugated protein and unrelated protein GAPDH in skeletal muscle of Tak1fl/fl and Tak1mKO mice. (H) Densitometry quantification of relative levels of ubiquitin-conjugated proteins. (I) Relative mRNA levels of MAFbx/Atrogin-1, MuRF1, Nedd4, and MUSA1 in skeletal muscle of Tak1fl/fl and Tak1mKO mice. (J) Relative mRNA levels of autophagy related genes LC3B, Beclin-1, Atg5, Gabarapl1, and Atg12 in skeletal muscle of Tak1fl/fl and Tak1mKO mice. (K) Representative immunoblots of LC3B-I/II and unrelated protein GAPDH in skeletal muscle of Tak1fl/fl and Tak1mKO mice. (L) Densitometry quantification of the ratio of LC3B-II vs. LC3B-I in skeletal muscle of Tak1fl/fl and Tak1mKO mice. n = 4 or 5 in each group. Error bars represent ± SEM. *P < 0.05 values significantly different from corresponding Tak1fl/fl mice by unpaired 2-tailed t test.

Copyright © 2026 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts