title: Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice.
abstract: 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.
  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.
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Chrysovalantou E
authors.initials: CE
authors.lastname: Xirouchaki
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Salvatore P
authors.initials: SP
authors.lastname: Mangiafico
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bate
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ruan
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Huang
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Bing Wilari
authors.initials: BW
authors.lastname: Tedjosiswoyo
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lamont
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Wynne
authors.initials: W
authors.lastname: Pong
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Favaloro
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Blair
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Zajac
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Proietto
authors.affiliation: University of Melbourne, Department of Medicine (Austin Health), Heidelberg, Victoria, 3084, Australia. Electronic address: sof@unimelb.edu.au.
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
keywords: Exercise capacity; Glucose tolerance; Inducible muscle-specific knockout (KO) mice; Insulin sensitivity; Muscle glucose uptake; gys1