Inhibition of calpain results in impaired contraction-stimulated GLUT4 translocation in skeletal muscle.
It was previously found that transgenic mice that overexpress the calpain inhibitor calpastatin (CsTg) have an approximately 3-fold increase in GLUT4 protein in their skeletal muscles. Despite the increase in GLUT4, which appears to be due to inhibition of its proteolysis by calpain, insulin-stimulated glucose transport is not increased in CsTg muscles. PKB (Akt) protein level is reduced approximately 60% in CsTg muscles, suggesting a possible mechanism for the relative insulin resistance. Muscle contractions stimulate glucose transport by a mechanism that is independent of insulin signaling. The purpose of this study was to test the hypothesis that the threefold increase in GLUT4 in CsTg would result in a large increase in contraction-stimulated glucose transport. CAMKII and AMPK mediate steps in the contraction-stimulated pathway. The protein levels of AMPK and CAMKII were increased three- to fourfold in CsTg muscles, suggesting that these proteins are also calpain substrates. Despite the large increases in GLUT4, AMPK, and CAMKII, contraction-stimulated GLUT4 translocation and glucose transport were not increased above wild-type values. These findings suggest that inhibition of calpain results in impairment of a step in the GLUT4 translocation process downstream of the insulin- and contraction-signaling pathways. They also provide evidence that CAMKII and AMPK are calpain substrates.
Otani
Kenichi
K
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Polonsky
Kenneth S
KS
Holloszy
John O
JO
Han
Dong-Ho
DH
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000378:metabolism* / Q000502:physiology; D003847:Deoxyglucose / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D051275:Glucose Transporter Type 4 / Q000032:analysis / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*
D002135:Calcium-Binding Proteins; D051275:Glucose Transporter Type 4; D009097:Multienzyme Complexes; C495693:Slc2a4 protein, mouse; C033668:calpastatin; D006003:Glycogen; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D002154:Calpain