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 11

TRAF6 is required for satellite cell proliferation and self-renewal following transplantation in dystrophic muscle.

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TRAF6 is required for satellite cell proliferation and self-renewal foll...
TA muscle of 8-week-old mdx mice was injured by i.m. injection of 100 μl 1.2% BaCl2 solution. After 24h, the muscle was injected with 1 × 106 mG;Traf6+/+ or mG;Traf6–/– cells. After 28 days, the TA muscle was isolated and processed for histological analysis. (A) Representative photomicrograph demonstrating mG-labeled fibers originating from mG;Traf6+/+ and mG;Traf6–/– cells in TA muscle sections of mdx mice. Scale bars: 20 μm. (B) Quantification of number of mG+ fibers in TA muscle of mdx mice. (C) Self-renewal of mG;Traf6+/+ and mG;Traf6–/– satellite cells was analyzed by immunostaining with PAX7 and DAPI. (D) Quantification of number of mG+;PAX7+ cells. Error bars represent SD. n = 4 in each group. *P < 0.05 (vs. TA muscle of mdx mice transplanted with mG;Traf6+/+ cells) by unpaired t test.