miR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle

Here, we identify miR-339-5p as a previously unrecognized, conserved regulator of skeletal muscle remodeling. Transcriptomic analysis from human, mouse, and rat studies revealed that miR-339-5p is consistently upregulated in skeletal muscle under conditions of stress or injury and declines during myogenic differentiation in vitro.

Gain-of-function experiments demonstrated that miR-339-5p overexpression impairs expression of genes associated with myogenic differentiation and promotes expression of proliferative markers in both primary human myotubes and mouse C2C12 cells. Transcriptomic profiling confirmed widespread repression of pathways involved in cytoskeletal organization, myofibrillar assembly, and mitochondrial function. In vivo, electroporation-mediated overexpression of miR-339-5p in mouse tibialis anterior altered regeneration-associated gene expression and increased the number of immature fibers, therefore modulating tissue remodeling during post-injury growth.