Nucleus Type-Specific DNA Methylomics Reveals Epigenetic “Memory” of Prior Adaptation in Skeletal Muscle

Author:

Wen Yuan12,Dungan Cory M23,Mobley C Brooks12,Valentino Taylor12,von Walden Ferdinand4ORCID,Murach Kevin A256ORCID

Affiliation:

1. Department of Physiology, University of Kentucky, Lexington, KY 40508, USA

2. The Center for Muscle Biology, University of Kentucky, Lexington, KY 40536, USA

3. College of Health Sciences, University of Kentucky, Lexington, KY 40536, USA

4. Division of Pediatric Neurology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm 171 77, Sweden

5. Molecular Muscle Mass Regulation Laboratory, Exercise Science Research Center, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR 72701, USA

6. Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR 72701, USA

Abstract

Abstract Using a mouse model of conditional and inducible in vivo fluorescent myonuclear labeling (HSA-GFP), sorting purification of nuclei, low-input reduced representation bisulfite sequencing (RRBS), and a translatable and reversible model of exercise (progressive weighted wheel running, PoWeR), we provide the first nucleus type-specific epigenetic information on skeletal muscle adaptation and detraining. Adult (>4 mo) HSA-GFP mice performed PoWeR for 8 wk then detrained for 12 wk; age-matched untrained mice were used to control for the long duration of the study. Myonuclei and interstitial nuclei from plantaris muscles were isolated for RRBS. Relative to untrained, PoWeR caused similar myonuclear CpG hypo- and hyper-methylation of promoter regions and substantial hypomethylation in interstitial nuclear promoters. Over-representation analysis of promoters revealed a larger number of hyper- versus hypo-methylated pathways in both nuclear populations after training and evidence for reciprocal regulation of methylation between nucleus types, with hypomethylation of promoter regions in Wnt signaling-related genes in myonuclei and hypermethylation in interstitial nuclei. After 12 wk of detraining, promoter CpGs in documented muscle remodeling-associated genes and pathways that were differentially methylated immediately after PoWeR were persistently differentially methylated in myonuclei, along with long-term promoter hypomethylation in interstitial nuclei. No enduring gene expression changes in muscle tissue were observed using RNA-sequencing. Upon 4 wk of retraining, mice that trained previously grew more at the whole muscle and fiber type-specific cellular level than training naïve mice, with no difference in myonuclear number. Muscle nuclei have a methylation epi-memory of prior training that may augment muscle adaptability to retraining.

Funder

NIH National Institutes on Aging

Publisher

Oxford University Press (OUP)

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