Signaling balance of MCTs and GPR81 controls lactate-induced metabolic function and cell death in skeletal muscle cells through Ranbp3l/Nfat5 and Atf4

Lactate, a byproduct of pyruvate in the glycolytic pathway, has been recognized as a signaling molecule and a regulator of gene expression. In skeletal muscles, lactate is dynamically regulated during exercise and influences muscular function, including myogenic differentiation and metabolism. The effects of lactate vary depending on lactate levels, which are influenced by exercise intensity, type, and duration. Furthermore, the effects of lactate on cellular signaling are different during the stages of myogenic differentiation. However, the distribution of lactate signaling in terms of lactate concentration, signaling types, and myogenesis has not been fully elucidated. In this study, we investigated the dual effects of lactate on myogenic differentiation and viability using C2C12 cells and C57BL/6 mice. Low levels of lactate treatment promoted myogenesis in the early stage of C2C12 differentiation, while high lactate concentrations or treatment with 3,5-DHBA, a GPR81 agonist, impaired cell viability during late myogenic differentiation. Transcriptomic analysis and knockdown experiments revealed that lactate promotes myogenesis and muscular metabolic functions through the induction of Ranbp3l and Nfat5 expressions. On the other hand, the detrimental effects of lactate on cell survival are mediated by the GPR81-induced PI3K-Akt/ERK-Atf4 axis. GPR81 signaling also feeds forward the expression of Hcar1 via Akt and ERK. These dual actions of lactate on skeletal muscle were also observed in vivo through lactate or 3,5-DHBA injections and exercise training models. Our study concludes that maintaining a balance in lactate signaling is crucial for regulating skeletal muscle phenotypes in response to exercise and lactate treatments.