Succinate Regulates Exercise-Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1

Background

Skeletal muscle remodelling can cause clinically important changes in muscle phenotypes. Satellite cells (SCs) myogenic potential underlies the maintenance of muscle plasticity. Accumulating evidence shows the importance of succinate in muscle metabolism and function. However, whether succinate can affect SC function and subsequently coordinate muscle remodelling to exercise remains unexplored.

Methods

A mouse model of high-intensity interval training (HIIT) was used to investigate the effects of succinate on muscle remodelling and SC function by exercise capacity test and biochemical methods. Mice with succinate receptor 1 (SUCNR1)-specific knockout in SCs were generated as an in vivo model to explore the underlying mechanisms. RNA sequencing of isolated SCs was performed to identify molecular changes responding to succinate-SUCNR1 signalling. The effects of identified key molecules on the myogenic capacity of SCs were investigated using gain- and loss-of-function assays in vitro. To support the translational application, the clinical efficacy of succinate was explored in muscle-wasting mice.

Results

After 21 days of HIIT, mice supplemented with 1.5% succinate exhibited striking gains in grip strength (+0.38 ± 0.04 vs. 0.26 ± 0.03 N, p < 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, p < 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (p < 0.001). The myogenic capacity of SCs was significantly increased in gastrocnemius muscle of mice supplemented with 1% and 1.5% succinate (+16.48% vs. control, p = 0.008; +47.25% vs. control, p < 0.001, respectively). SUCNR1-specific deletion in SCs abolished the modulatory influence of succinate on muscle adaptation in response to exercise, revealing that SCs respond to succinate–SUCNR1 signalling, thereby facilitating muscle remodelling. SUCNR1 signalling markedly upregulated genes associated with stem cell differentiation and phosphorylation pathways within SCs, of which p38α mitogen-activated protein kinase (MAPK; fold change = 6.7, p < 0.001) and protein kinase C eta (PKCη; fold change = 12.5, p < 0.001) expressions were the most enriched, respectively. Mechanistically, succinate enhanced the myogenic capacity of isolated SCs by activating the SUCNR1–PKCη–p38α MAPK pathway. Finally, succinate promoted SC differentiation (1.5-fold, p < 0.001), ameliorating dexamethasone-induced muscle atrophy in mice (p < 0.001).

Conclusions

Our findings reveal a novel function of succinate in enhancing SC myogenic capacity via SUCNR1, leading to enhanced muscle adaptation in response to exercise. These findings provide new insights for developing pharmacological strategies to overcome muscle atrophy–related diseases.