Recurrent training rejuvenates and enhances transcriptome and methylome responses in young and older human muscle

Abstract

BackgroundThe interaction between the muscle methylome and transcriptome is understudied during ageing and periods of resistance training in young, but especially older adults. More information is needed on the role of retained methylome training adaptations in muscle memory to understand muscle phenotypical and molecular restoration after inactivity or disuse. Methods We measured CpG methylation (microarray) and RNA expression (RNA sequencing) in young (n = 5; age = 22 ± 2 years) and older (n = 6; age = 65 ± 5 years) vastus lateralis muscle samples, taken at baseline, after 12 weeks of resistance training, after training interruption (2 weeks of leg immobilization in young men, 12 weeks of detraining in older men) and after 12 weeks of retraining to identify muscle memory-related adaptations and rejuvenating effects of training. ResultsWe report that of the 427 differentially expressed genes with advanced age (FDR < 0.1), 71% contained differentially methylated (dm)CpGs in older versus young muscle (FDR < 0.1, M-value difference >0.4). The more dmCpGs within a gene, the clearer the inverse methylation-expression relationship. Around 73% of the age-related dmCpGs approached younger methylation levels when older muscle was trained for 12 weeks. A second resistance training period after training cessation increased the number of hypomethylated CpGs and upregulated genes in both young and older muscle. We found indication for an epi-memory within pro-proliferating AMOTL1 in young muscle and mechanosensing-related VCL in older muscle. For the first time, we integrate muscle methylome and transcriptome data in relation to both ageing and training-induced/inactivity-induced responses and identify focal adhesion as an important pathway herein. Conclusions This preliminary evidence indicates that previously trained muscle is more responsive to training than untrained muscle at methylome and transcriptome level and recurrent resistance training can partially restore ageing-induced methylome alterations.

Late‐life exercise mitigates skeletal muscle epigenetic aging

“…In some instances, chronological age is less associated with muscle dysfunction than other related factors such as body mass or cardiorespiratory fitness (Distefano et al, 2017 ). Nevertheless, the attenuation of muscle epigenetic aging by exercise supports recent targeted observations in humans (Blocquiaux et al, 2021 ; Ruple et al, 2021 ) and adds to the growing body of evidence touting exercise as a strategy to extend healthspan. Our work provides potentially modifiable epigenetic markers for improving muscle health with age once the mechanistic bases of dynamic DNA methylation alterations in muscle fibers are more clearly defined (Small et al, 2021 ).…”

Aerobic Exercise Training Rejuvenates the Human Skeletal Muscle Methylome Ten Years after Breast Cancer Treatment and Survival

“…aerobic [35] vs. resistance [17,18] vs. high intensity exercise [34]) promote this hypomethylation of divergent genes and pathways. Exercise has therefore been proposed to be epigenetically 'anti-ageing' [28,29,[36][37][38][39]. Where we have also demonstrated that resistance exercise can reset the mitochondrial methylome in elderly individuals [36] and others have demonstrated this in aged humans and mice where resistance exercise and power weighted wheel running, respectively, can help return DNA methylation signatures back towards those observed in younger individuals [29,37].…”

Aging, Skeletal Muscle, and Epigenetics

“…Indeed, work by Blocquiaux et al questioned whether increased physical activity in the form of resistance exercise could prevent age-related epigenetic changes. 33 Similar DNA methylome studies to those in young adult humans described above via training were performed, but also included cast immobilization and later retraining in older participants. The authors confirmed that aged muscle tissue was hypermethylated compared with young adult muscle at baseline and also confirmed that some genes demonstrated retained methylation signatures from earlier training into detraining and retraining, suggestive of an epigenetic memory of exercise in aged muscle.…”

“…They also suggested that training was able to return 73% of CpGs in aged muscle (hypermethylated) back toward levels seen in the young adults at baseline (hypomethylated), and that retraining enhanced this effect further. 33 Therefore, suggesting that exercise could rejuvenate the aged skeletal muscle methylome toward signatures observed in younger adults. Finally, we also demonstrated this rejuvenation effect of exercise on the DNA methylome in the mitochondria of aged skeletal muscle.…”