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

Abstract

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 À/À) or muscle-specific deletion of the accessory protein Basigin (iMSBsg À/À). Although MCT4 À/À and iMSBsg À/À mice have normal muscle morphology and contractility, only MCT4 À/À mice exhibit an exercise intolerant phenotype. In vivo measurements of compound muscle action potentials showed a decrement in the evoked response in the MCT4 À/À 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.

Role of monocarboxylate transporters in regulating metabolic homeostasis in the outer retina: Insight gained from cell‐specific Bsg deletion

“…Previous studies have shown that Bsg1 is preferentially expressed in photoreceptors, while Bsg2 is widely expressed in most other cells . Bsg floxed mice were generated by insertion of floxed sites on either side of exon 1 . Targeted deletion of exon 1 ensured that neither splice variant of Bsg would be expressed (Figure A).…”

“…Mice carrying a floxed Bsg allele were crossed to transgenic mice expressing Cre recombinase in rods (B6;SJL‐ Pde6b + Tg(Rho‐iCre)1Ck/Boc JAX stock #015850) or cones (Tg(Opn1mw‐cre)1Asw) or RPE (C57BL/6‐Tg(BEST1‐cre)1Jdun/J) to generate mice lacking Bsg in rods ( Bsg flox/flox ; Rho‐iCre; hereafter RodΔBsg ) or cones ( Bsg flox/flox ; coneCre; hereafter ConeΔBsg ) or RPE ( Bsg flox/flox ; Best1‐Cre ; hereafter RPEΔBsg ) and control littermates ( Bsg flox/+ Cre positive ; Bsg flox/flox Cre negative; hereafter control). To generate mice lacking Bsg in both rod and cone photoreceptors, ConeΔBsg and RodΔBsg were crossed to generate Cone/RodΔBsg .…”

Mct11 deficiency alters hepatic glucose metabolism and energy homeostasis

“…While further investigation is needed to confirm the role of MCT11 in lactate transport, our data suggest MCT11 may be the primary MCT responsible for lactate export from hepatocytes residing in the low oxygen pericentral region. This would be analogous to the role of SLC16A3 /MCT4 in muscle, which is induced by hypoxia-inducible factor 1 (HIF1) and mediates lactate efflux under glycolytic, anaerobic conditions such as experienced during hypoxia and exercise (Bisetto et al, 2019; Contreras-Baeza et al, 2019; Ullah et al, 2006). Beyond the MCT family, our findings underscore the importance of delineating cell populations and contexts where genes are expressed and the value in modeling relevant cellular contexts when investigating gene function.…”