MiR-27b-3p reduces muscle fibrosis during chronic skeletal muscle injury by targeting tgf-βr1/smad3 pathway

Abstract

Abstract Fibrosis is a significant pathological manifestation of chronic skeletal muscle injury, and excessive deposition of extracellular matrix severely impacts muscle regeneration. Fibro-adipogenic progenitors (FAPs) are able to differentiate into myofibroblasts, serving as a source of the extracellular matrix.Despite there is a certain understanding of the function and differentiation of FAPs,the mechanisms underlying the fibrogenic differentiation of FAPs during chronic skeletal muscle injury still require further investigation.In this study,It was found that muscle-derived FAPs in the sciatic nerve transection mouse model exhibited a fibrotic phenotype that worsened over time. Subsequently, we investigated miRNAs that may have significant effects on fibrosis of FAPs. The results revealed that miR-27b-3p abundance in FAPs decreased progressively as fibrosis intensified. Furthermore, application of miR-27b-3p mimics effectively suppressed fibrosis in vitro and in vivo.Lastly, the dual-luciferase reporter assay, overexpression or knockdown of tgf-βr1 and utilization of SIS3 (a smad3 phosphorylation inhibitor) demonstrated that miR-27b-3p targeted the tgf-βr1/smad3 pathway and that tgf-βr1/smad3 negatively regulated miR-27b-3p. Taken together, our study indicates that miR-27b-3p targeting the tgf-βr1/smad3 pathway is a novel mechanism for regulating fibrosis of FAPs. Increasing miR-27b-3p abundance, suppressing tgf-βr1 expression, and inhibiting smad3 phosphorylation present potential strategies for treating fibrosis in chronic skeletal muscle injury.