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TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis
Sajedah M. Hindi, Ashok Kumar
Sajedah M. Hindi, Ashok Kumar
Published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):151-168. https://doi.org/10.1172/JCI81655.
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Research Article Muscle biology Article has an altmetric score of 82

TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis

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Abstract

Satellite cells are a stem cell population within adult muscle and are responsible for myofiber regeneration upon injury. Satellite cell dysfunction has been shown to underlie the loss of skeletal muscle mass in many acquired and genetic muscle disorders. The transcription factor paired box-protein-7 (PAX7) is indispensable for supplementing the reservoir of satellite cells and driving regeneration in normal and diseased muscle. TNF receptor–associated factor 6 (TRAF6) is an adaptor protein and an E3 ubiquitin ligase that mediates the activation of multiple cell signaling pathways in a context-dependent manner. Here, we demonstrated that TRAF6-mediated signaling is critical for homeostasis of satellite cells and their function during regenerative myogenesis. Selective deletion of Traf6 in satellite cells of adult mice led to profound muscle regeneration defects and dramatically reduced levels of PAX7 and late myogenesis markers. TRAF6 was required for the activation of MAPKs ERK1/2 and JNK1/2, which in turn activated the transcription factor c-JUN, which binds the Pax7 promoter and augments Pax7 expression. Moreover, TRAF6/c-JUN signaling repressed the levels of the microRNAs miR-1 and miR-206, which promote differentiation, to maintain PAX7 levels in satellite cells. We also determined that satellite cell–specific deletion of Traf6 exaggerates the dystrophic phenotype in the mdx (a mouse model of Duchenne muscular dystrophy) mouse by blunting the regeneration of injured myofibers. Collectively, our study reveals an essential role for TRAF6 in satellite stem cell function.

Authors

Sajedah M. Hindi, Ashok Kumar

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Figure 3

Deletion of Traf6 in satellite cells inhibits formation of new myofibers and expression of MRFs following injury.

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Deletion of Traf6 in satellite cells inhibits formation of new myofibers...
(A) Representative photomicrographs of days 0, 3, and 5 injured TA muscle section of Traf6fl/fl and TRAF6scko mice after immunostaining for eMyHC. Nuclei were identified by staining with DAPI. Scale bars: 20 μm. (B) Quantification of number of eMyHC+ fibers per field (~0.15 mm2) in 5d injured TA muscle of Traf6fl/fl and TRAF6scko mice. (C) Average CSA of eMyHC+ fibers in 5d injured TA muscle. (D) Representative immunoblots demonstrating the protein levels of eMyHC and unrelated protein GAPDH in TA muscle of Traf6fl/fl and TRAF6scko mice at various time point after BaCl2 injection. (E and F) Relative mRNA levels of Myh3 (E) and Myf5, Myod, and myogenin (F) 3d after injury. Error bars represent SD. n = 5–6 in each group. *P < 0.05 (vs. injured TA muscle of Traf6fl/fl mice) by unpaired t test. †P < 0.05 (vs. corresponding uninjured TA muscle of Traf6fl/fl or TRAF6scko mice) by paired t test. #P < 0.05 (vs. uninjured TA muscle of Traf6fl/fl mice) by paired t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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