MiR-126-5p Derived From Bone Marrow Mesenchymal Stem Cell Exosomes Promotes Skeletal Muscle Regeneration by Regulating FBXO32/MyoD Signaling

Abstract

Aim

In the process of muscle growth and repair, microRNAs (miRNAs) serve as a critical factor in spatiotemporal regulation. Nevertheless, the molecular regulatory mechanisms underlying muscle regeneration remain largely unknown.

Methods

Exosomes from control and miR-126-knockdown BMSCs were isolated via ultracentrifugation. A mouse muscle injury model was established using 1.2% barium chloride in gastrocnemius muscles. Injured tissues received local injections of BMSC exosomes or AAV-miR-126. Gene expression was analyzed by qRT-PCR/Western blot. Tissue morphology and repair were assessed via H&E staining, while regeneration markers were evaluated through immunostaining.

Results

Here, we identified miR-126-5p in BMSC-derived exosomes as a positive regulator of muscle regeneration. These exosomes promoted the proliferation and maturation of myoblasts and facilitated the regeneration of skeletal muscle in male C57BL/6J mice. FBXO32 was confirmed as the downstream target of exosomal miR-126-5p to regulate skeletal muscle regeneration, and it ubiquitinated and degraded myogenic differentiation 1 (MyoD). Notably, miR-126-5p knockdown from BMSC-derived exosomes significantly inhibited proliferation and differentiation of Pax7⁺ SCs and muscle regeneration, whereas adeno-associated virus (AAV)-mediated overexpression of miR-126-5p accelerated these processes. Specifically, the BMSC-derived exosomes delivered miR-126-5p to skeletal muscle, thus decreasing the expression of FBXO32, in turn increasing MyoD expression, finally significantly promoting satellite cell differentiation and skeletal muscle regeneration.

Conclusions

BMSC-derived exosomes could promote skeletal muscle injury repair through miR-126-5p, and thus miR-126-5p may act as a molecular therapeutic target of skeletal muscle diseases. Elucidating functional mechanisms of exosomes and miRNA is of great significance for developing new biotherapy strategies for skeletal muscle disease.