Exercise-induced microRNAs: molecular pathways and adaptive remodeling of skeletal muscle

Abstract Exercise is an effective physiological stimulus that promotes vast structural and functional changes in skeletal muscular tissue. Although transcriptional pathways that control exercise-based plasticity have been studied in depth, recent findings highlight the importance of microRNAs (miRNAs) as an essential post-transcriptional control platform mediating contractile stimuli and molecular and physiologic adaptations. This review provides a synthesis of existing evidence on exercise responsive miRNAs at the systems level, and especially on the topic of skeletal muscle remodeling. The review outlines the effects of different exercise regimens such as endurance, resistance, and high-intensity interval training to dynamic miRNA response to regulate major biological pathways such as mitochondrial biogenesis, protein turnover, angiogenesis, inflammatory signaling, and metabolic regulation. Acute exercise is also typified by temporary changes in miRNAs, which facilitate short-term stress signalling, and chronic training leads to more long-term miRNA re-programming, which facilitates long-term structural and functional remodeling. Also, circulating and exosome-bound miRNAs are also mentioned as potential agents of the muscle-to-organ interaction, thus supporting the idea of skeletal muscle that acts like an endocrine-like organ during exercise. Besides narrative synthesis, the review is based on an exploratory, data-driven re-analysis of publicly available skeletal muscle miRNA sequencing data to define convergent regulatory programs instead of data-specific differentiation. This is observed under integrative pathway and network-level analysis which identifies coordinated miRNA modules linked to mitochondrial regulation, cytoskeletal remodeling, and inflammatory control. Taken together, this framework brings together non-homogenous evidence throughout the literature and highlights the prospect of exercise-sensitive miRNAs as systems-level regulators of skeletal muscle adaptation.