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.

Signaling pathways regulating the fate of fibro/adipogenic progenitors (FAPs) in skeletal muscle regeneration and disease

“…Ciliary Hh signaling in FAPs regulates the expression of the metalloprotease inhibitor Metalloproteinase inhibitor 3 (TIMP3) that represses adipogenesis by inhibiting Matrix metalloproteinase-14 (MMP14). Mimicking TIMP3 inhibitory role, through a pan-MMP inhibitor or by directly knocking down MMP14 restricts FAP adipogenesis in vitro and in vivo [35,113]. A recent investigation have revealed that Kruppel-like factor 6 (KLF6) is a transcription factor associated with MMP14 [113].…”

“…Mimicking TIMP3 inhibitory role, through a pan-MMP inhibitor or by directly knocking down MMP14 restricts FAP adipogenesis in vitro and in vivo [35,113]. A recent investigation have revealed that Kruppel-like factor 6 (KLF6) is a transcription factor associated with MMP14 [113]. KLF6 acts as an "on-off" switch in the differentiation of FAPs into adipocytes or alpha smooth muscle actin (-SMA)-expressing myofibroblasts.…”

Severe Muscle Deconditioning Triggers Early Extracellular Matrix Remodeling and Resident Stem Cell Differentiation into Adipocytes in Healthy Men

“…Cumulative data now shows that aging and chronic degenerative skeletal muscle diseases affect the muscle microenvironment composition, particularly muscle stem cells [ 20 , 27 ]. However, whether microgravity-induced hypoactivity can alter the muscle microenvironment is not known.…”

RNA-Seq Reveals Function of Bta-miR-149-5p in the Regulation of Bovine Adipocyte Differentiation

“…The cyclin D2 (CCND2) and Cdk2 are well-known proliferation marker genes, enriched in early differentiation and then again overexpressed in the later stage of adipocyte differentiation [ 94 , 95 ]. Kruppel-like factor 6 (KLF6) is a transcription factor and is a potent regulator of adipocyte differentiation [ 96 ]. ACSL1 is a proven mediator of lipid metabolism, cellular lipid content, and insulin sensitivity in adipocyte differentiation [ 97 ].…”