Muscle-Specific Ablation of Glucose Transporter 1 (GLUT1) Does Not Impair Basal or Overload-Stimulated Skeletal Muscle Glucose Uptake

Abstract

Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle [3H]-2-deoxyglucose uptake ± the GLUT1 inhibitor BAY-876. [3H]-hexose uptake ± BAY-876 was also examined in HEK293 cells-expressing GLUT1-6 or GLUT10. mGLUT1KO mice exhibited no impairments in body weight, lean mass, whole body metabolism, glucose tolerance, basal or overload-stimulated muscle glucose uptake. There was no compensation by the insulin-responsive GLUT4. In mGLUT1KO mouse muscles, overload stimulated higher expression of mechanosensitive GLUT6, but not GLUT3 or GLUT10. In control and mGLUT1KO mouse muscles, 0.05 µM BAY-876 impaired overload-stimulated, but not basal glucose uptake. In the GLUT-HEK293 cells, BAY-876 inhibited glucose uptake via GLUT1, GLUT3, GLUT4, GLUT6, and GLUT10. Collectively, these findings demonstrate that GLUT1 does not mediate basal muscle glucose uptake and suggest that a novel glucose transport mechanism mediates overload-stimulated glucose uptake.

Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle

“…Genetic deletion of GLUT1 specifically in the skeletal muscle was confirmed previously by the Witczak lab. 13 Additionally, our lab confirmed the reduction of GLUT1 mRNA in single FDB muscle fibers via RT-PCR (PowerTrack SYBR Green #A46109, ThermoFisher) in a similar fashion as previously described using primer sequences for GLUT1 (SLC2A1) and HAGH. 13 No differences were detected in the FDB muscles between the MCK-Cre + (control) and GLUT1 fl/fl (WT) in a preliminary investigation; thus, GLUT1 fl/fl were used as WT mice for the present study.…”

“… 36 Our data confirm another lab’s demonstration of GLUT1 deletion in the skeletal muscle of the GLUT1 KO mice. 13 To determine whether GLUT1 is necessary for the FDB to maintain force output during anoxia, we repeated the 3-h contractile protocol described above in WT and GLUT1 KO muscles. Deletion of GLUT1 in the FDB resulted in loss of force output, as the FD 50 in the KO group was reached at 135 min of anoxia exposure, whereas the FD 50 did not occur in anoxic WT muscles ( Figure 7C ).…”

“… 10 A key difference in the study by Schmidt et al 10 is the greater work performed by the muscles during the contractile protocol as compared to our protocol, thus implying greater energetic demand, and potentially explaining lower glycogen content. Also surprisingly, McMillin et al 13 recently demonstrated that neither glucose uptake nor glycogen content is altered in skeletal muscles that lack GLUT1 expression, suggesting a complicated role for GLUT1 in skeletal muscle. Our resulting data provide equivocal evidence that pharmacological inhibition of glycolysis via BrP results in loss of FDB force production during anoxia exposure; however, the muscle does not appear to catabolize greater amounts of glucose.…”