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

We describe a pH-sensing metabolite signal that initiates muscle remodeling upon 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 S. Carl; Kim A. Sjøberg; Jørgen F.P. Wojtaszewski; Jacob F. Jeppesen; Bente Kiens; Steven P. Gygi; Erik A. Richter; Diane Mathis; Edward T. Chouchani

2020

Scholarcy highlights

  • Skeletal muscle remodeling in response to exercise has multiple systemic health benefits in mice and humans
  • Samples were gated on three criteria: metabolite accumulation immediately post-exercise in local muscle extracellular fluid; metabolite enrichment in muscle interstitial fluid compared with total muscle tissue; local enrichment in local muscle extracellular fluid compared with bulk circulation
  • Together, our findings define a bioenergetic mechanism in muscle that senses intracellular pH, using succinate to communicate local energetic status to the peripheral tissue environment
  • Neurotrophic and muscle ECM remodeling initiated upon exercise depend essentially on paracrine succinate-SUCNR1 signaling, which is required for major physiologic and molecular adaptations to exercise training
  • Our data demonstrate a role for succinate-SUCNR1 paracrine regulation in muscle, it is possible that autocrine regulation could play a role in some contexts
  • We did not detect SUCNR1 in intact muscle by in situ hybridization, it is possible that, following certain types of exercise training or fiber type remodeling, that SUCNR1 is expressed in these cell types as well

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