Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1: Influence of the genetic background

Abstract

A prediabetic phenotype of glucose intolerance, insulin resistance and obesity was observed at ∼ 12 months age in age nice homozygous for a null allele of the major skeletal muscle glycogen-targeting subunit GM of protein phosphatase 1 (PP1) and derived from a 129/Ola donor strain. In this study, backcrossing of these GM-/- mice (termed obese GM-/- mice) onto two different genetic backgrounds gave rise to lean, glucose-tolerant, insulin-sensitive GM-+- mice (termed lean GM-/- 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 GM-/- mice. Slightly elevated AMP-activated protein kinase α2 activity in the skeletal muscle of lean C57BL/6 GM-/- mice was also observed to a lesser extent in the obese GM-/- mice. Normal or slightly raised in vivo glucose transport in lean C57BL/6 GM-/- mice compared with decreased glucose transport in the obese GM-/- 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 GM-/- mice compared with controls indicating that phosphorylase kinase is an in vivo substrate of PP1-GM. © 2008 Society for Endocrinology.