Indirect regulation of HIPPO pathway by miRNA mediates high‐intensity intermittent exercise to ameliorate aging skeletal muscle function

Exercise‐induced microRNA (miRNA) and HIPPO pathways participate in the regulation of skeletal muscle plasticity but their underlying mechanisms remain unclear. We aimed to investigate the effect of high‐intensity interval training (HIIT) on miRNA expression and the HIPPO pathway in the skeletal muscle of aging rats to determine its role in the amelioration of muscle aging. Thirty‐six 18‐month‐old female rats were randomly divided into sedentary control (SED, n = 12), moderate‐intensity continuous training (MICT, n = 12), and HIIT ( n = 12) groups, with continuous exercise for 8 months. Quantitative reverse transcription‐polymerase chain reaction, immunoblotting, KEGG enrichment, and dual‐luciferase assays were performed on the target skeletal muscle. Compared with the SED group, the MICT and HIIT groups showed a significant trend of improvement in Lee's index and grip strength and a marked increase in skeletal muscle mitochondrial function, apoptosis, antioxidant, and lipolysis‐related protein expression. They also exhibited PI3K/AKT pathway activation and a decrease in expression of HIPPO pathway‐related proteins; 20 miRNAs were differentially expressed and enriched in the exercise group compared with the SED group, including the HIPPO pathway and metabolic pathways. Further analysis of L6 cells confirmed that miR‐182 may target PTEN, which indirectly regulates HIPPO signaling, but not Mob1. the combined application of HIIT and MICT increased the antioxidant and lipolytic capacities of skeletal muscle and improved atrophy of aging skeletal muscle; HIIT was more effective than MICT. This may be related to HIIT‐mediated AKT pathway activation and HIPPO pathway inhibition by miRNAs (miR‐486 and miR‐182).