pH-gated succinate secretion regulates muscle remodeling in response to exercise

Anita Reddy, Luiz H M Bozi, Omar K Yaghi, Evanna L Mills, Haopeng Xiao, Hilary E Nicholson, Margherita Paschini, Joao A Paulo, Ryan Garrity, Dina Laznik-Bogoslavski, Julio C B Ferreira, Christian Strini Carl, Kim Anker Sjøberg, Jørgen Wojtaszewski, Jacob F Jeppesen, Bente Kiens, Steven P Gygi, Erik A. Richter, Diane Mathis, Edward T Chouchani*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

136 Citations (Scopus)
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Abstract

In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.

Original languageEnglish
JournalCell
Volume183
Issue number1
Pages (from-to)62-75, e1-e10
Number of pages32
ISSN0092-8674
DOIs
Publication statusPublished - 2020

Bibliographical note

Copyright © 2020 Elsevier Inc. All rights reserved.

Keywords

  • Faculty of Science
  • SUCNR1
  • Exercise
  • Innervation
  • Muscle
  • Succinate

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