mir‐22‐3p/KLF6/MMP14 axis in fibro‐adipogenic progenitors regulates fatty infiltration in muscle degeneration

Abstract Fibro/adipogenic progenitors (FAPs) are the main cellular source of fatty degeneration in muscle injury; however, the underlying mechanism of FAP adipogenesis in muscle degeneration needs to be further examined. Matrix metalloproteinase 14 (MMP‐14) has been reported to induce the adipogenesis of 3T3‐L1 preadipocytes, but whether MMP‐14 also regulates the differentiation of FAPs remains unclear. To investigate whether and how MMP‐14 regulates FAP adipogenesis and fatty infiltration in muscle degeneration, we examined MMP‐14 expression in degenerative muscles and tested the effect of MMP‐14 on FAP adipogenesis in vitro and in vivo. As expected, MMP‐14 enhanced FAP adipogenesis and fatty infiltration in degenerative muscles; moreover, blocking endogenous MMP‐14 in injured muscles facilitated muscle repair. Further investigations revealed that Kruppel‐like factor 6 (KLF6) was a transcription factor associated with MMP‐14 and acted as an “on‐off” switch in the differentiation of FAPs into adipocytes or myofibroblasts. Moreover, KLF6 was the target gene of miR‐22‐3p, which was downregulated during FAP adipogenesis both in vitro and in vivo, and overexpression of miR‐22‐3p markedly prevented FAP adipogenesis and attenuated fatty degeneration in muscles. Our study revealed that miR‐22‐3p/KLF6/MMP‐14 is a novel pathway in FAP adipogenesis and that inhibiting KLF6 is a potential strategy for the treatment of muscular degenerative diseases.