Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as an AMPK substrate regulating skeletal muscle function

Ronnie Blazev, Christian Strini Carl, Yaan-Kit Ng, Jeffrey Molendijk, Christian Thomas Voldstedlund, Yuanyuan Zhao, Di Xiao, Andrew J Kueh, Paula M Miotto, Vanessa R Haynes, Justin P Hardee, Jin D Chung, James W McNamara, Hongwei Qian, Paul Gregorevic, Jonathan S Oakhill, Marco J Herold, Thomas Elbenhardt Jensen, Leszek Lisowski, Gordon S LynchGarron T Dodd, Matthew J Watt, Pengyi Yang, Bente Kiens*, Erik A. Richter*, Benjamin L Parker*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

35 Citations (Scopus)

Abstract

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.

Original languageEnglish
JournalCell Metabolism
Volume34
Issue number10
Pages (from-to)1561-1577.e9
Number of pages27
ISSN1550-4131
DOIs
Publication statusPublished - 2022

Bibliographical note

Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.

Keywords

  • Faculty of Science
  • Exercise
  • Skeletal muscle
  • Phosphoproteomics
  • AMPK
  • C18ORF25
  • Signaling

Cite this