Examining the role of succinate signaling in tissue remodeling

Abstract

While the benefits of exercise on systemic health are undeniable, vigorous muscle contraction, like the ones associated with exercise, puts considerable mechanical and energetic strain on muscle fibers. To meet these newfound demands, skeletal muscle must undergo extensive remodeling. This is a highly coordinated process that involves the participation of numerous non-myofibril cell populations such as satellite cells, stromal cells, immune cells, and endothelial cells. How exercising muscle communicates with these cells to initiate the remodeling process remains poorly understood. We performed comparative metabolomics analysis on exercised skeletal muscle to identify potential signaling molecules that preferentially increase in the local extracellular environment of muscle, following exercise. Using this approach, we identified succinate, a tricarboxylic acid (TCA) cycle intermediate, as a potential exercise signaling molecule in both mice and humans. Succinate is a ligand for a g-protein coupled receptor, succinate receptor 1 (SUCNR1). Using a hybrid resistance-endurance training model, we implicate succinate-SUCNR1 signaling in a host of remodeling processes such as fast-twitch myosin protein expression, innervation, and extracellular matrix remodeling. These changes manifest as a SUCNR1-dependent increase in strength. Additionally, we show that SUCNR1 is exclusively localized to non-myofibrillar cells within skeletal muscle. Moreover, we identify a novel pH-gated transport mechanism for succinate where monocarboxylate transporter 1 (MCT1) is repurposed to allow for succinate secretion from skeletal muscle, during exercise. We also show this transport mechanism to be relevant in brown adipose tissue (BAT) where succinate sequestration by BAT has been linked to many favorable outcomes including reduced systemic tissue inflammation and increased energy expenditure. Overall, we identify a novel role for succinate as an exercise-responsive metabolite, implicate succinate-SUCNR1 signaling in many muscle remodeling processes, and characterize a new transport mechanism for succinate.