Abstract
Skeletal muscle has remarkable regeneration capacity and regenerates in response to injury. Muscle regeneration largely relies on muscle stem cells called satellite cells. Satellite cells normally remain quiescent, but in response to injury or exercise they become activated and proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Interestingly, the inflammatory process following injury and the activation of the myogenic program are highly coordinated, with myeloid cells having a central role in modulating satellite cell activation and regeneration. Here, we show that genetic deletion of microRNA-155 (miR-155) in mice substantially delays muscle regeneration. Surprisingly, miR-155 does not appear to directly regulate the proliferation or differentiation of satellite cells. Instead, miR-155 is highly expressed in myeloid cells, is essential for appropriate activation of myeloid cells, and regulates the balance between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages during skeletal muscle regeneration. Mechanistically, we found that miR-155 suppresses SOCS1, a negative regulator of the JAK-STAT signaling pathway, during the initial inflammatory response upon muscle injury. Our findings thus reveal a novel role of miR-155 in regulating initial immune responses during muscle regeneration and provide a novel miRNA target for improving muscle regeneration in degenerative muscle diseases.
Highlights
Mammalian skeletal muscle is capable of repairing itself following exercise or injury
We have previously reported that microRNA-155 represses myogenic differentiation by targeting MEF2A, a key myogenic transcription factor, in C2C12 cells.[31]
Using genetic deletion of miR-155,37,38 we showed that miR-155 facilitates skeletal muscle regeneration by regulating appropriate activation of macrophages
Summary
Mammalian skeletal muscle is capable of repairing itself following exercise or injury. Upon muscle damage or disease, these quiescent stem cells immediately become activated, proliferate, migrate to the injured site, and differentiate to fuse with damaged myofibers or to form new myofibers.[1,2,3,4] The regeneration of adult skeletal muscle is a highly coordinated process involving a variety of cell types and signaling molecules that work systematically to repair the damaged myofibers.[2,6,7,8] how this process is regulated by muscle stem cell niche cues, such as inflammatory signals after muscle injury, still remains elusive. The subsequent transition of myeloid infiltration into anti-inflammatory M2 macrophages is critical for the overall resolution of inflammation in the injured muscles.[8,14,15,16,18] loss of balance between these two different types. Together with a previous report on miR-21 function in macrophage transitions,[43] our data support the notion that a macrophageenriched miRNA can indirectly have profound effects on skeletal muscle regeneration, providing a novel small RNA target for designing therapies for muscle injury and degenerative muscle diseases
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