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

• Published in: Cell Vol. 183; no. 1; pp. 62 - 75.e17
• Main Authors: Reddy, Anita, Bozi, Luiz H.M., Yaghi, Omar K., Mills, Evanna L., Xiao, Haopeng, Nicholson, Hilary E., Paschini, Margherita, Paulo, Joao A., Garrity, Ryan, Laznik-Bogoslavski, Dina, Ferreira, Julio C.B., Carl, Christian S., Sjøberg, Kim A., Wojtaszewski, Jørgen F.P., Jeppesen, Jacob F., Kiens, Bente, Gygi, Steven P., Richter, Erik A., Mathis, Diane, Chouchani, Edward T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2020
• Subjects: Animals; exercise; Humans; Hydrogen-Ion Concentration; Inflammation - metabolism; innervation; Mice; Mitochondria - metabolism; Monocarboxylic Acid Transporters - metabolism; muscle; Muscle Contraction; Muscle, Skeletal - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, G-Protein-Coupled - physiology; Signal Transduction; succinate; Succinates - metabolism; Succinic Acid - metabolism; SUCNR1; Symporters - metabolism; succinate; exercise; SUCNR1; innervation; muscle
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.08.039

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.
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•Mouse and human muscle selectively release succinate during exercise•Muscle cells release succinate by pH-gated secretion via MCT1•Extracellular succinate regulates paracrine responses to exercise through SUCNR1•SUCNR1 signaling mediates muscle remodeling responses to exercise training
Reddy et al. identify a bioenergetic sensor that uses pH and succinate to regulate muscle tissue adaptation to exercise.