Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
TAK1 regulates skeletal muscle mass and mitochondrial function
Sajedah M. Hindi, … , Shizuka Uchida, Ashok Kumar
Sajedah M. Hindi, … , Shizuka Uchida, Ashok Kumar
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e98441. https://doi.org/10.1172/jci.insight.98441.
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 1

TAK1 is required for post-natal skeletal muscle growth in mice.

Options: View larger image (or click on image) Download as PowerPoint
TAK1 is required for post-natal skeletal muscle growth in mice.
(A) Sche...
(A) Schematic representation of WT TAK1 and kinase domain-truncated (green) TAK1 protein. (B) Treatment protocol for tamoxifen-induced Cre recombination in Tak1mKO mice. Six-week-old Tak1fl/fl and Tak1mKO mice were given i.p. injections of tamoxifen, and 3 weeks later, the mice were analyzed. (C) Gross appearance of Tak1fl/fl and Tak1mKO mice. (D) Average body weight of Tak1fl/fl and Tak1mKO mice. (E) Average forelimb and (F) average 4-paw grip strength in Tak1fl/fl and Tak1mKO mice normalized by their body weight. (G) Representative images of skinned Tak1fl/fl and Tak1mKO mice. Arrow pointing to kyphotic phenotype in Tak1mKO mice. (H) Average weight of soleus (Sol), gastrocnemius (GA), tibialis anterior (TA), quadriceps (Quad), and extensor digitorum longus (EDL) muscles in Tak1fl/fl and Tak1mKO mice. (I) Representative photomicrographs of TA muscle sections of Tak1fl/fl and Tak1mKO mice after staining for H&E (top panel) and anti-laminin (lower panel). Scale bars: 20 μm. Quantification of (J) average myofiber CSA, and (K) mean minimal Feret’s diameter in TA and soleus muscle sections of Tak1fl/fl and Tak1mKO mice. (L) PCR analysis of genomic DNA from GA muscle of tamoxifen-treated Tak1fl/fl and Tak1mKO mice using primer sets that detect truncated TAK1 and TNF receptor 1 (TNFR1). Representative PCR gel images presented here demonstrate efficient deletion of the kinase domain of TAK1 in Tak1mKO mice following tamoxifen administration. (M) Immunoblots presented here demonstrate that the protein levels of TAK1, but not TAB1 or TRAF6, were diminished in GA muscle of Tak1mKO mice. n = 6 or 7 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 © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts