Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival

Abstract

Cancer survivors suffer impairments in skeletal muscle in terms of reduced mass and function. Interestingly, human skeletal muscle possesses an epigenetic memory of earlier stimuli, such as exercise. Long‐term retention of epigenetic changes in skeletal muscle following cancer survival and/or exercise training has not yet been studied. We, therefore, investigated genome‐wide DNA methylation (methylome) in skeletal muscle following a 5‐month, 3/week aerobic‐training intervention in breast cancer survivors 10–14 years after diagnosis and treatment. These results were compared to breast cancer survivors who remained untrained and to age‐matched controls with no history of cancer, who undertook the same training intervention. Skeletal muscle biopsies were obtained from 23 females before(pre) and after(post) the 5‐month training period. InfiniumEPIC 850K DNA methylation arrays and RT‐PCR for gene expression were performed. The breast cancer survivors displayed a significant retention of increased DNA methylation (i.e., hypermethylation) at a larger number of differentially methylated positions (DMPs) compared with healthy age‐matched controls pre training. Training in cancer survivors led to an exaggerated number of DMPs with a hypermethylated signature occurring at non‐regulatory regions compared with training in healthy age‐matched controls. However, the opposite occurred in important gene regulatory regions, where training in cancer survivors elicited a considerable reduction in methylation (i.e., hypomethylation) in 99% of the DMPs located in CpG islands within promoter regions. Importantly, training was able to reverse the hypermethylation identified in cancer survivors back toward a hypomethylated signature that was observed pre training in healthy age‐matched controls at 300 (out of 881) of these island/promoter‐associated CpGs. Pathway enrichment analysis identified training in cancer survivors evoked a predominantly hypomethylated signature in pathways associated with cell cycle, DNA replication/repair, transcription, translation, mTOR signaling, and the proteosome. Differentially methylated region (DMR) analysis also identified genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104, and SPG7 as hypermethylated in breast cancer survivors, with training reversing these CpG island/promoter‐associated DMRs toward a hypomethylated signature. Training also elicited a largely different epigenetic response in healthy individuals than that observed in cancer survivors, with very few overlapping changes. Only one gene, SIRT2, was identified as having altered methylation in cancer survivors at baseline and after training in both the cancer survivors and healthy controls. Overall, human skeletal muscle may retain a hypermethylated signature as long as 10–14 years after breast cancer treatment/survival. Five months of aerobic training reset the skeletal muscle methylome toward signatures identified in healthy age‐matched individuals in gene regulatory regions.

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

“…In this study, the authors did not use clocks but investigated all DNAm loci that change with age in mouse muscle and applied a direct exercise training intervention. A couple of human studies are in line with these results: resistance training was shown to offset age‐related changes both in the nuclear (Blocquiaux et al, 2022 ; Gorski et al, 2023 ) and mitochondrial (Ruple et al, 2021 ) epigenome. Unfortunately, these studies had small sample sizes and have not been replicated to date, so they should be regarded as preliminary (Fanelli et al, 2017 ).…”

Skeletal muscle DNA methylation: Effects of exercise and HIV

“…Thus, variation in methylation due to HIV serostatus was selected out when using MEAT but was apparent in the genome-wide analyses (Figure 2). In line with this rationale, no study using MEAT, including the present one, has identified associations between SkM epigenetic age and sarcopenia (Antoun et al, 2022), physical function (Sillanpaa et al, 2021) or exercise training (Gorski et al, 2023).…”

“…The sample size was insufficient for sub-analyses of exercise mode-or intensity-effects on SkM DNA methylation or to measure pathway enrichment. Although the number of unique individuals included in our study is equivalent to or greater than several other studies investigating the impact of exercise intervention on SkM DNAm (Garcia et al, 2022;Gorski et al, 2023;Lindholm et al, 2014), our sample size precluded the examination of potential effect modifiers such as classes of ART used in the past and during the study;…”

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

“…In this study, the authors did not use clocks but investigated all DNA methylation loci that change with age in mouse muscle and applied a direct exercise training intervention. A couple of human studies are in line with these results: resistance training was shown to offset age-related changes both in the nuclear 21,22 and mitochondrial 23 epigenome. Unfortunately, these studies had small sample sizes and have not been replicated to date, so they should be regarded as preliminary 24 .…”

“…A couple of human studies are in line with these results: resistance training was shown to offset age-related changes both in the nuclear 21,22 and mitochondrial 23 epigenome. Unfortunately, these studies had small sample sizes and have not been replicated to date, so they should be regarded as preliminary 24 .…”