Epigenetic evidence for distinct contributions of resident and acquired myonuclei during long-term exercise adaptation using timed in vivo myonuclear labeling

K. A. Murach, C. M. Dungan, F. von Walden, Y. Wen

Research output: Contribution to journalArticlepeer-review


Muscle fibers are syncytial postmitotic cells that can acquire exogenous nuclei from resident muscle stem cells, called satellite cells. Myonuclei are added to muscle fibers by satellite cells during conditions such as load-induced hypertrophy. It is difficult to dissect the molecular contributions of resident versus satellite cell-derived myonuclei during adaptation due to the complexity of labeling distinct nuclear populations in multinuclear cells without label transference between nuclei. To sidestep this barrier, we used a genetic mouse model where myonuclear DNA can be specifically and stably labeled via nonconstitutive H2B-GFP at any point in the lifespan. Resident myonuclei (Mn) were GFP-tagged in vivo before 8 wk of progressive weighted wheel running (PoWeR) in adult mice (>4-mo-old). Resident + satellite cell-derived myonuclei (Mn+SC Mn) were labeled at the end of PoWeR in a separate cohort. Following myonuclear isolation, promoter DNA methylation profiles acquired with low-input reduced representation bisulfite sequencing (RRBS) were compared to deduce epigenetic contributions of satellite cell-derived myonuclei during adaptation. Resident myonuclear DNA has hypomethylated promoters in genes related to protein turnover, whereas the addition of satellite cell-derived myonuclei shifts myonuclear methylation profiles to favor transcription factor regulation and cell-cell signaling. By comparing myonucleus-specific methylation profiling to previously published single-nucleus transcriptional analysis in the absence (Mn) versus the presence of satellite cells (Mn+SC Mn) with PoWeR, we provide evidence that satellite cell-derived myonuclei may preferentially supply specific ribosomal proteins to growing myofibers and retain an epigenetic "memory" of prior stem cell identity. These data offer insights on distinct epigenetic myonuclear characteristics and contributions during adult muscle growth.
Original languageAmerican English
Pages (from-to)C86-C93
JournalAmerican Journal of Physiology - Cell Physiology
Issue number1
StatePublished - 2022

Bibliographical note

Murach, Kevin A Dungan, Cory M von Walden, Ferdinand Wen, Yuan eng R00 AG063994/AG/NIA NIH HHS/ K99 AG063994/AG/NIA NIH HHS/ R01 AR060701/AR/NIAMS NIH HHS/ R01 DK119619/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Am J Physiol Cell Physiol. 2022 Jan 1;322(1):C86-C93. doi: 10.1152/ajpcell.00358.2021. Epub 2021 Nov 24.


  • Adaptation, Physiological/*physiology Animals Cell Nucleus/chemistry/*metabolism Epigenesis, Genetic/*physiology Green Fluorescent Proteins/analysis/metabolism Male Mice Mice, Transgenic Muscle Fibers, Skeletal/chemistry/*metabolism Physical Conditioning, Animal/methods/*physiology Satellite Cells, Skeletal Muscle/chemistry/metabolism Staining and Labeling/*methods Time Factors *DNA methylation *rrbs *hypertrophy *satellite cells


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