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

TY - JOUR

T1 - Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1

T2 - influence of the genetic background

AU - Paterson, James

AU - Kelsall, Ian R.

AU - Cohen, Patricia T. W.

PY - 2008/2

Y1 - 2008/2

N2 - 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 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 mice. Slightly elevated AMP-activated protein kinase a2 activity in the skeletal muscle of lean C57BL/6 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.

AB - 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 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 mice. Slightly elevated AMP-activated protein kinase a2 activity in the skeletal muscle of lean C57BL/6 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.

KW - AMP-Activated Protein Kinases

KW - Adipose Tissue

KW - Animals

KW - Crosses, Genetic

KW - Environment

KW - Female

KW - Glucose

KW - Glucose Tolerance Test

KW - Glycogen

KW - Hindlimb

KW - Isoenzymes

KW - Liver

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Multienzyme Complexes

KW - Muscle, Skeletal

KW - Phenotype

KW - Protein Phosphatase 1

KW - Protein Subunits

KW - Protein-Serine-Threonine Kinases

KW - Thinness

U2 - 10.1677/JME-07-0120

DO - 10.1677/JME-07-0120

M3 - Article

C2 - 18234908

SN - 0952-5041

VL - 40

SP - 47

EP - 59

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

IS - 2

ER -