Exercise‐related <scp>microRNAs</scp> in <i>Caenorhabditis elegans</i> regulate calcium homeostasis and mitochondrial dynamics: Conserved pathways, divergent <scp>microRNAs</scp>

Exercise can help mitigate age-related muscle atrophy, promoting mitochondrial function, Ca²⁺ homeostasis and regulating gene expression. MicroRNAs (miRs) are crucial post-transcriptional regulators of gene expression, fine-tuning protein levels to maintain cellular homeostasis. In Caenorhabditis elegans, a 5-day swimming regimen increased mitochondrial content, lifespan and fitness. Small RNA sequencing identified exercise specific miRs, including increased levels of cel-miR-57-5p and cel-miR-249-3p, and decreased levels of cel-miR-72-3p and cel-miR-77-5p. mir-57 and mir-249 mutant strains had enhanced fertility, survival and lifespan, whereas mir-72 and mir-77 mutant strains had diminished fertility, survival and lifespan. The exercise-related miRs identified in C. elegans did not have conserved mammalian orthologs. Exercise regulated mammalian miRs were identified from the literature including mmu-miR-181a-5p, mmu-miR-199a-5p and mmu-miR-378a-3p. Treatment of murine myoblasts with mmu-miR-181a-5p and mmu-miR-378a-3p enhanced mitochondrial content, autophagy markers and myogenesis, while mmu-miR-199a-5p impaired these processes. Exercise-related miRs identified in C. elegans target genes regulating Ca²⁺ homeostasis such as ipp-5 (inositol Polyphosphate-5-phosphatase), sca-1 (Ca²⁺ transporting ATPase) and ncx-2 (mitochondrial Na⁺/Ca²⁺ antiporter). It was also confirmed that mmu-miR181a-5p targets Inpp5a and treatment with antogmiR-181a decreased Ca²⁺ handling in myotubes. Similarly, mmu-miR-378a-3p and cel-miR-249-3p target Kinase Suppressor of Ras (Ksr1)/ksr-2, involved in the MAPK pathway. Despite direct conservation of exercise-related miRs from nematodes to mammals, there are putative common regulatory pathways contributing to exercise-induced adaptations.