The stimulation-induced increase in skeletal muscle glycogen synthase content is impaired in carriers of the glycogen synthase XbaI gene polymorphism

Associations between glycogen synthase gene (GYS1) polymorphism and states of insulin resistance and type 2 diabetes have been reported. The purpose o f this study was to establish if the GYS1 genotype impacts on the content o f glycogen synthase (GS) protein in muscle measured under basal and stimula ted conditions. To examine this, GYS1 XbaI and Met416Val polymorphisms and thigh muscle GYS1 protein content were determined at rest, both before and after several weeks of neuromuscular electrical stimulation in carriers and noncarriers of the mutations. The allelic frequency was 0.086 for the XbaI mutation (A2) and 0.006 for the Met416Val in our cohort of French-Canadian subjects. When measured at rest, the GS protein content in muscle was simi lar among carriers and noncarriers of the XbaI variant. However, the stimul ation-induced increase (23%) in the amount of GS muscle protein normally se en in wild-type individuals was impaired in those carrying the XbaI mutatio n. These data demonstrate that some individuals, because of their genetic b ackground, are unable to stimulate the process of GS protein accumulation i n skeletal muscle. These results could explain why some individuals appear to be genetically predisposed to developing skeletal muscle insulin resista nce when exposed to unfavorable metabolic environments.