New Insights into the Lactate Shuttle: Role of MCT4 in the Modulation of the Exercise Capacity

Summary

Lactate produced by muscle during high-intensity activity is an important end product of glycolysis that supports whole body metabolism. The lactate shuttle model suggested that lactate produced by glycolytic muscle fibers is utilized by oxidative fibers. MCT4 is a proton coupled monocarboxylate transporter preferentially expressed in glycolytic muscle fibers and facilitates the lactate efflux. Here we investigated the exercise capacity of mice with disrupted lactate shuttle due to global deletion of MCT4 (MCT4 ^−/−) or muscle-specific deletion of the accessory protein Basigin (iMSBsg ^−/−). Although MCT4 ^−/− and iMSBsg ^−/− mice have normal muscle morphology and contractility, only MCT4 ^−/− mice exhibit an exercise intolerant phenotype. In vivo measurements of compound muscle action potentials showed a decrement in the evoked response in the MCT4 ^−/− mice. This was accompanied by a significant structural degeneration of the neuromuscular junctions (NMJs). We propose that disruption of the lactate shuttle impacts motor function and destabilizes the motor unit.

Graphical Abstract

Highlights

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  MCT4 facilitates lactate efflux from the cells and is highly expressed in muscles fibers

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  MCT4 ^−/− mice are exercise intolerant but there is no impact on muscle physiology

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  Action Potential conduction is impaired in the MCT4 ^−/− mice and NMJs are disrupted

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  MCT4 and lactate efflux play a role in the maintenance of a functional motor unit

Abstract

Musculoskeletal Medicine; Genetics; Neuroscience