Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise

Vandré C. Figueiredo, Yuan Wen, Björn Alkner, Rodrigo Fernandez-Gonzalo, Jessica Norrbom, Ivan J. Vechetti, Taylor Valentino, C. Brooks Mobley, Gabriel E. Zentner, Charlotte A. Peterson, John J. McCarthy, Kevin A. Murach, Ferdinand von Walden

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Key points: Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery. A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE. Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter. Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans. A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage. Abstract: Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 ± 8 years, 25 ± 4 kg m–2) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% (Formula presented.)) or resistance exercise (n = 10, 4 × 7 × 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non-canonical MYC-associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc-associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene-wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation.

Original languageEnglish
Pages (from-to)3363-3384
Number of pages22
JournalJournal of Physiology
Volume599
Issue number13
DOIs
StatePublished - Jul 1 2021

Bibliographical note

Funding Information:
The study was funded by Futurum – the Academy for Health and Care, Region Jönköping County, Sweden to BA and the Swedish Kidney Foundation and Swedish Research Council for Sports to FvW, and a National Institutes of Health grant (NIH K99 AG063994) to KAM.

Funding Information:
The study was funded by Futurum???the Academy for Health and Care, Region J?nk?ping County, Sweden to BA and the Swedish Kidney Foundation and Swedish Research Council for Sports to FvW, and a National Institutes of Health grant (NIH K99 AG063994) to KAM. We thank the subjects for their extraordinary effort and participation. We further greatly acknowledge the help from staff at H?glandssjukhuset District Hospital in Eksj? where the human study took place, especially Annica Eriksson, Lena Norrbrand, Bj?rn Otto and the personnel at the Orthopaedic Department. We wish to thank Jennifer Strange of the University of Kentucky Flow Cytometry Core, Dr Ann-Charlotte R?nn of the Karolinska Institutet Mutation Analysis Facility (EpiTyper analysis) and Dr Keith Booher at Zymo Research. The graphical abstract was generated using BioRender (https://biorender.com).

Publisher Copyright:
© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society

Keywords

  • CpG methylation
  • Myc
  • enhancer
  • intergenic spacer
  • rDNA
  • rDNA copy number

ASJC Scopus subject areas

  • Physiology

Fingerprint

Dive into the research topics of 'Genetic and epigenetic regulation of skeletal muscle ribosome biogenesis with exercise'. Together they form a unique fingerprint.

Cite this