pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise

Cell. 2020 Oct 1;183(1):62-75.e17. doi: 10.1016/j.cell.2020.08.039.

Anita Reddy ¹, Luiz H M Bozi ², Omar K Yaghi ³, Evanna L Mills ¹, Haopeng Xiao ¹, Hilary E Nicholson ⁴, Margherita Paschini ⁵, Joao A Paulo ⁶, Ryan Garrity ⁷, Dina Laznik-Bogoslavski ⁷, Julio C B Ferreira ⁸, Christian S Carl ⁹, Kim A Sjøberg ⁹, Jørgen F P Wojtaszewski ⁹, Jacob F Jeppesen ¹⁰, Bente Kiens ⁹, Steven P Gygi ⁶, Erik A Richter ⁹, Diane Mathis ³, Edward T Chouchani ¹¹

Affiliations

1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
3 Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
5 Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
8 Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
9 Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
10 Global Drug Discovery, Novo Nordisk A/S, Copenhagen, Denmark.
11 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].

PMID: 32946811 DOI: 10.1016/j.cell.2020.08.039

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.

Keywords

SUCNR1; exercise; innervation; muscle; succinate.

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