Abstract
Quiescent satellite cells (SCs) that are activated to produce numerous myoblasts underpin the complete healing of damaged skeletal muscle. How cell-autonomous regulatory mechanisms modulate the balance among cells committed to differentiation and those committed to self-renewal to maintain the stem cell pool remains poorly explored. Here, we show that miR-31 inactivation compromises muscle regeneration in adult mice by impairing the expansion of myoblasts. miR-31 is pivotal for SC proliferation, and its deletion promotes asymmetric cell fate segregation of proliferating cells, resulting in enhanced myogenic commitment and re-entry into quiescence. Further analysis revealed that miR-31 posttranscriptionally suppresses interleukin 34 (IL34) mRNA, the protein product of which activates JAK–STAT3 signaling required for myogenic progression. IL34 inhibition rescues the regenerative deficiency of miR-31 knockout mice. Our results provide evidence that targeting miR-31 or IL34 activities in SCs could be used to counteract the functional exhaustion of SCs in pathological conditions.
Highlights
These authors contributed : Yang Su, Yingying YuThese authors jointly supervised this work: Zhengquan Yu, Qingyong MengEdited by M
JAK–STAT3 signaling in satellite cells (SCs) increases with age and leads to a decline in cell function through stimulation of asymmetric cell division [20]. All of these findings indicated that JAK–STAT3 activity in SCs has an important role in modulating cell fate segregation; the upstream effectors that control the activity of JAK–STAT3 signaling in adult proliferating SCs during muscle regeneration remain poorly understood
Previous studies have reported that the transcription level of miR-31 in activated SCs is upregulated [32], indicating that miR-31 is pivotal for the cell-autonomous regulatory mechanisms of activated SCs, which is in line with our in situ hybridization and qRT-PCR analyses, both of which further revealed that miR-31 was upregulated in injured muscle (Fig. 1a, b)
Summary
Profile analysis of Duchenne muscular dystrophy compared with wild-type (WT) muscles revealed that miR31 showed a 50-fold enrichment relative to control samples [33] All of these findings indicated that miR-31 plays important roles in regulating activated SCs. In this study, we show that mice with miR-31 deletion have deficient skeletal muscle repair in response to 1.2% BaCl2 injury. Inefficient regeneration results from the impaired expansion of SCs and relates to the dysregulation of IL34, a cell-autonomous positive regulator of JAK–STAT3 signaling, which impairs the function of SCs through the stimulation of asymmetric division. TA muscles from recipient WT mice transplanted with SCs with miR-31 deletion displayed a clear reduction in muscle regeneration (Fig. 1m, n) These results suggest that miR-31 is essential for the early stage of skeletal muscle regeneration
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