Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1: influence of the genetic background.
A prediabetic phenotype of glucose intolerance, insulin resistance and obesity was observed at approximately 12 months of age in mice homozygous for a null allele of the major skeletal muscle glycogen-targeting subunit G(M) of protein phosphatase 1 (PP1) and derived from a 129/Ola donor strain. In this study, backcrossing of these G(M)-/- mice (termed obese G(M)-/- mice) onto two different genetic backgrounds gave rise to lean, glucose-tolerant, insulin-sensitive G(M)-/- mice (termed lean G(M)-/- mice), indicating that at least one variant gene in the 129/Ola background, not present in the C57BL/6 or 129s2/sV background, is required for the development of the prediabetic phenotype of obese mice. Slightly elevated AMP-activated protein kinase alpha2 activity in the skeletal muscle of lean C57BL/6 mice was also observed to a lesser extent in the obese G(M)-/- mice. Normal or slightly raised in vivo glucose transport in lean C57BL/6 G(M)-/- mice compared with decreased glucose transport in the obese G(M)-/- mice supports the tenet that adequate transport of glucose may be a key factor in preventing the development of the prediabetic phenotype. The pH 6.8/pH 8.6 activity ratio of phosphorylase kinase was increased in lean C57BL/6 G(M)-/- mice compared with controls indicating that phosphorylase kinase is an in vivo substrate of PP1-G(M).
Paterson
James
J
Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Kelsall
Ian R
IR
Cohen
Patricia T W
PT
D055372:AMP-Activated Protein Kinases; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003433:Crosses, Genetic; D004777:Environment; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism*; D006614:Hindlimb / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology*; D010641:Phenotype; D054645:Protein Phosphatase 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D013851:Thinness
D007527:Isoenzymes; D009097:Multienzyme Complexes; D021122:Protein Subunits; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D054645:Protein Phosphatase 1; D005947:Glucose