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
Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model
Anirban Roy, Tatiana E. Koike, Aniket S. Joshi, Meiricris Tomaz da Silva, Kavya Mathukumalli, Mingfu Wu, Ashok Kumar
Anirban Roy, Tatiana E. Koike, Aniket S. Joshi, Meiricris Tomaz da Silva, Kavya Mathukumalli, Mingfu Wu, Ashok Kumar
View: Text | PDF
Research Article Muscle biology Therapeutics

Targeted regulation of TAK1 counteracts dystrophinopathy in a DMD mouse model

  • Text
  • PDF
Abstract

Muscular dystrophies make up a group of genetic neuromuscular disorders that involve severe muscle wasting. TGF-β–activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeletal muscle of adult mice. However, the role of TAK1 in muscle diseases remains poorly understood. In the present study, we have investigated how TAK1 affects the progression of dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). TAK1 is highly activated in the dystrophic muscle of mdx mice during the peak necrotic phase. While targeted inducible inactivation of TAK1 inhibits myofiber injury in young mdx mice, it results in reduced muscle mass and contractile function. TAK1 inactivation also causes loss of muscle mass in adult mdx mice. By contrast, forced activation of TAK1 through overexpression of TAK1 and TAB1 induces myofiber growth without having any deleterious effect on muscle histopathology. Collectively, our results suggest that TAK1 is a positive regulator of skeletal muscle mass and that targeted regulation of TAK1 can suppress myonecrosis and ameliorate disease progression in DMD.

Authors

Anirban Roy, Tatiana E. Koike, Aniket S. Joshi, Meiricris Tomaz da Silva, Kavya Mathukumalli, Mingfu Wu, Ashok Kumar

×

Figure 4

Effect of inactivation of TAK1 on myofiber regeneration in mdx mice.

Options: View larger image (or click on image) Download as PowerPoint
Effect of inactivation of TAK1 on myofiber regeneration in mdx mice.
Fou...
Four-week-old mdx;Tak1fl/fl and mdx;Tak1mKO mice were treated with tamoxifen and analyzed at the age of 8 weeks. Transverse sections of TA muscle were immunostained for Pax7 and Laminin. Nuclei was counterstained with DAPI. (A and B) Representative photomicrographs and quantitative analysis showing frequency of Pax7+ cells in TA muscle of 8-week-old littermate mdx;Tak1fl/fl and mdx;Tak1mKO mice. n = 4 per group. Data represented as mean ± SEM. *P ≤ 0.05, values significantly different mdx;Tak1fl/fl mice by Student t test. (C–E) Transverse sections of GA muscle were immunostained for eMyHC and Laminin. Nuclei were counterstained with DAPI. (C) Representative photomicrographs and quantitative analysis of (D) average myofiber cross-section area of eMyHC+ myofibers and (E) percentage of eMyHC+ myofibers in 8-week-old mdx;Tak1fl/fl and mdx;Tak1mKO mice. n = 4 per group. (F and G) Western blot and densitometry analysis showing protein levels of eMyHC, MyoD, and unrelated protein GAPDH. n = 6. Data represented as mean ± SEM. *P ≤ 0.05, values significantly different from mdx;Tak1fl/fl mice by Student t test. (H–J) Following TAK1 inactivation in adult Tak1fl/fl and Tak1mKO mice, TA muscle was injected 100 μL of 10 μM cardiotoxin solution. (H) Representative photomicrographs of H&E-stained TA muscle sections and quantification of (I) average myofiber cross-section area (CSA) and (J) percentage of centronucleated fibers (CNFs). n = 4–5 per group. Data represented as mean ± SEM. Western blots for F, Figure 5E, and Figure 6E were performed contemporaneously. Black lines on the immunoblots indicate that intervening lanes have been spliced out.

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

Sign up for email alerts