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

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

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 2

TRAF6 is required for skeletal muscle regeneration.

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TRAF6 is required for skeletal muscle regeneration. (A) Representative p...
(A) Representative photomicrographs of H&E-stained sections illustrating a severe regeneration defect in injured TA muscle of TRAF6scko mice compared with Traf6fl/fl littermates at indicated time points after BaCl2 injection. Scale bars: 20 μm. (B) Quantification of number of CNF per field (~0.15 mm2) at day 5 after injury. (C) Number of myofibers containing more than 1 central nuclei per field (~0.15 mm2) at day 5 after injury. (D) Average CSA of regenerating myofibers at day 5 after injury. After 21 days of first injury, TA muscle of Traf6fl/fl and TRAF6scko mice was again given i.m. injection of 100 μl of 1.2% BaCl2 solution, and the muscle was analyzed at day 5. (E and F) Representative photomicrograph of H&E-stained TA muscle section (E), and trichrome-stained TA-stained muscle sections (F). Scale bar: 20 μm. Error bars represent SD. n = 6 per group for day 5 after single injury and n = 3 per group for all other time points. *P < 0.01 (vs. injured TA muscle of Traf6fl/fl mice) by unpaired t test.