Impaired exercise capacity in muscle-specific Gys1- KO mice. — ASN Events
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Impaired exercise capacity in muscle-specific Gys1- KO mice. (#15)

Chrysovalantou E Xirouchaki , Salvatore P Mangiafico , Zheng Ruan , Amy M Huang , Joseph Proietto , Sof Andrikopoulos

We have previously presented at this meeting that muscle-specific deletion of glycogen synthase 1 gene (gys1) in the mouse caused glucose intolerance and insulin resistance. The aim of the present study is to determine whether a muscle-specific deletion of gys1 would also impair exercise and endurance capacity, as well as whether a bout of exercise can reverse the glucose intolerance of the Gys1-KO mice. Ten week-old mice were fed a diet containing 1 mg/g tamoxifen for 8 weeks followed by a 4-week recovery period on tamoxifen-free chow diet. Gys1-KO mice displayed 88% muscle gys1 mRNA and >85% muscle gys1 deletion leading to 70% reduced muscle glycogen levels. There was no difference in body weight, heart weight and food intake. Gys1-KO mice showed impaired exercise and endurance capacity (30% reduction in maximal exercise speed, 45% decrease in exercise workload, and 70% reduction in endurance) compared with control mice after a 6-hour and an overnight fasting period respectively. Postprandial and post-exercise plasma glucose and lactate levels were increased in Gys1-KO mice. Pre and post-exercise glucose tolerance tests showed that a bout of exercise had no impact on glucose tolerance for both of the groups. Mechanistic studies investigating the link between gys1 deletion, impaired glucose tolerance and exercise capacity showed increased liver glycogen concentration, a trend for increased muscle pdk4 mRNA as well as reduced muscle hexokinase II and glucose-6-phosphate levels. In summary, our study demonstrates that a muscle-specific gys1 deletion results in impaired exercise and endurance capacity which can be attributed to a principal defect in muscle function. Furthermore, the current study shows that a bout of high-intensity exercise cannot reverse the glucose intolerance/insulin resistance caused by the principal genetic defect. In conclusion, our study elucidates the crucial role of gys1 and muscle glycogen in muscle function and exercise capacity, exploring a physiological mechanism linking muscle-specific gys1 deletion with impaired glucose and exercise metabolism.

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