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

Kevin A. Murach, Cory M. Dungan, Ferdinand von Walden, Yuan Wen

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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 þ satellite cell-derived myonuclei (Mn þ 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 þ 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 languageEnglish
Pages (from-to)C86-C93
JournalAmerican Journal of Physiology - Cell Physiology
Volume322
Issue number1
DOIs
StatePublished - Jan 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 the American Physiological Society.

Keywords

  • DNA methylation
  • Hypertrophy
  • RRBS
  • Satellite cells

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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