MicroRNA Regulated Transcriptomic Changes during Aging in Human Skeletal Muscle Are Reversible with Exercise Training

Muscle mass declines with age (sarcopenia) in both men and women resulting in impaired physical function and altered glucose metabolism. Endurance exercise training can mitigate and even reverse some of the changes in skeletal muscle structure and function, which are observed at advanced age. To gain insight into the potential mechanisms driving sarcopenia and the adaptive response to training, we conducted deep sequencing on vastus lateralis muscle obtained from healthy, younger (n=14; age=27±0.89 y; 8 women, 6 men) and older (n=14, age=71±1.39 y; 7 women, 7 men) subjects before and after a 4 month endurance training program. We analyzed the sequencing data with bioinformatics tools to determine whether miRNAs that change with age can be reverted back to youthful levels with training. We found that skeletal muscle from women had 7 miRNAs and men had 8 miRNAs that changed with age and were reverted back to youthful levels with training, respectively. In older trained females these 7 miRNAs targeted 94 unique transcripts in the top 1000 differentially expressed genes between post-training compared to pre-training and these transcripts were involved in lipid metabolism, glycolysis, and growth. In older men the 8 miRNAs with youthful signatures after training had 146 unique targets involved in phosphoprotein and PI3K-AKT signaling, as well as cholinergic synapses. Notably, miR-29b-3p was primarily responsible for the regulation of target transcripts within the PI3K-AKT pathway in older trained men; similar family members (miR-29a-3p and miR-29c-3p) have been directly linked to insulin sensitivity in preclinical models. All miRNAs with youthful signatures in older trained subjects had opposing expression patterns to their target mRNAs. We conclude that some of the aging related changes to the skeletal muscle transcriptome are under the regulation of miRNAs and that exercise training can reverse these changes. Disclosure J. Valentine: None. S. Ghosh: None. B. Milholland: None. J.A. Gelfond: None. N. Musi: None.