Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice
| Autor: | Sofianos Andrikopoulos, Jeffrey D Zajac, Wynne Pong, Bing Wilari Tedjosiswoyo, Benjamin J. Lamont, Zheng Ruan, Katherine Bate, Jenny M Favaloro, Joseph Proietto, Chrysovalantou E. Xirouchaki, Salvatore P. Mangiafico, Amy M. Huang, Amy R. Blair |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty lcsh:Internal medicine Glucose uptake 030209 endocrinology & metabolism Carbohydrate metabolism Muscle glucose uptake Glycogen debranching enzyme Impaired glucose tolerance 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Internal medicine medicine Exercise capacity gys1 Inducible muscle-specific knockout (KO) mice Glycogen synthase lcsh:RC31-1245 Molecular Biology biology Glycogen business.industry Skeletal muscle Glucose tolerance Cell Biology medicine.disease Insulin sensitivity 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry biology.protein Original Article business |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 5, Iss 3, Pp 221-232 (2016) |
| ISSN: | 2212-8778 |
| Popis: | Objective Muscle glucose storage and muscle glycogen synthase (gys1) defects have been associated with insulin resistance. As there are multiple mechanisms for insulin resistance, the specific role of glucose storage defects is not clear. The aim of this study was to examine the effects of muscle-specific gys1 deletion on glucose metabolism and exercise capacity. Methods Tamoxifen inducible and muscle specific gys-1 KO mice were generated using the Cre/loxP system. Mice were subjected to glucose tolerance tests, euglycemic/hyperinsulinemic clamps and exercise tests. Results gys1-KO mice showed ≥85% reduction in muscle gys1 mRNA and protein concentrations, 70% reduction in muscle glycogen levels, postprandial hyperglycaemia and hyperinsulinaemia and impaired glucose tolerance. Under insulin-stimulated conditions, gys1-KO mice displayed reduced glucose turnover and muscle glucose uptake, indicative of peripheral insulin resistance, as well as increased plasma and muscle lactate levels and reductions in muscle hexokinase II levels. gys1-KO mice also exhibited markedly reduced exercise and endurance capacity. Conclusions Thus, muscle-specific gys1 deletion in adult mice results in glucose intolerance due to insulin resistance and reduced muscle glucose uptake as well as impaired exercise and endurance capacity. In brief This study demonstrates why the body prioritises muscle glycogen storage over liver glycogen storage despite the critical role of the liver in supplying glucose to the brain in the fasting state and shows that glycogen deficiency results in impaired glucose metabolism and reduced exercise capacity. Graphical abstract Highlights • Muscle-specific gys1 knockdown in adult mice results in 70% reduction in skeletal muscle glycogen levels. • Muscle-specific gys1 knockdown leads to glucose intolerance and peripheral insulin resistance. • Muscle glycogen depletion caused impaired performance, as well as fatigue development during exercise. |
| Databáze: | OpenAIRE |
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