Physiological functions of MCT1 and MCT4 in intramuscular lactate shuttle, exercise performance, and glucose disposal.

Lactate shuttling between glycolytic and oxidative muscle fibers via monocarboxylate transporters MCT1 and MCT4 is fundamental to muscle energy homeostasis, yet the physiological necessity of these two transporters remained obscured by functional redundancy. To investigate the significance of these two transporters in intermuscular lactate shuttle, we generated and characterized skeletal muscle-specific MCT1/4 double-knockout (MCT1/4-mKO) mice alongside with MCT4 single-knockout mice (MCT4-mKO). Although MCT4-mKO mice had minimal metabolic disturbances, MCT1/4-mKO mice exhibited markedly reduced lean mass, impaired exercise endurance, together with enhanced insulin-stimulated glucose disposal under normal chow diet conditions. The blood lactate level after exercise and the maximum grip strength were mitigated in both MCT4-mKO and MCT1/4-mKO mice. Plasma membrane localization of GLUT4 was robustly increased in the skeletal muscle in MCT1/4-mKO mice upon insulin treatment. These findings highlight that the intramuscular lactate shuttle mediated by MCT1 and MCT4 is critical for maintaining skeletal muscle mass, contractile performance, and insulin sensitivity.NEW & NOTEWORTHY The lactate shuttle within skeletal muscle is crucial for muscle functions, especially during exercise. It has long been proposed that two lactate transporters called MCT1 and MCT4 are involved in the lactate shuttle in the skeletal muscles. This study provides direct evidence that these two transporters are involved in maintaining the physiology and exercise performance of the skeletal muscle by utilizing a mouse model with muscle-specific ablation of these two lactate transporters.