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). While MCT4-mKO mice had minimal metabolic disturbances, MCT1/4-mKO mice exhibited markedly reduced lean mass, impaired exercise endurance together with enhancement of insulin-stimulated glucose disposal under normal chow diet condition. The blood lactate level after exercise and the maximum grip strength was 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.