Integrin-linked kinase stabilizes myotendinous junctions and protects muscle from stress-induced damage.
Skeletal muscle expresses high levels of integrin-linked kinase (ILK), predominantly at myotendinous junctions (MTJs) and costameres. ILK binds the cytoplasmic domain of beta1 integrin and mediates phosphorylation of protein kinase B (PKB)/Akt, which in turn plays a central role during skeletal muscle regeneration. We show that mice with a skeletal muscle-restricted deletion of ILK develop a mild progressive muscular dystrophy mainly restricted to the MTJs with detachment of basement membranes and accumulation of extracellular matrix. Endurance exercise training enhances the defects at MTJs, leads to disturbed subsarcolemmal myofiber architecture, and abrogates phosphorylation of Ser473 as well as phosphorylation of Thr308 of PKB/Akt. The reduction in PKB/Akt activation is accompanied by an impaired insulin-like growth factor 1 receptor (IGF-1R) activation. Coimmunoprecipitation experiments reveal that the beta1 integrin subunit is associated with the IGF-1R in muscle cells. Our data identify the beta1 integrin-ILK complex as an important component of IGF-1R/insulin receptor substrate signaling to PKB/Akt during mechanical stress in skeletal muscle.
Wang
Hao-Ven
HV
Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Chang
Ling-Wei
LW
Brixius
Klara
K
Wickström
Sara A
SA
Montanez
Eloi
E
Thievessen
Ingo
I
Schwander
Martin
M
Müller
Ulrich
U
Bloch
Wilhelm
W
Mayer
Ulrike
U
Fässler
Reinhard
R
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D019012:Integrin beta1 / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000293:injuries* / Q000378:metabolism* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D013710:Tendons / Q000378:metabolism* / Q000473:pathology; D000099200:Scaffold Protein ILK
D019012:Integrin beta1; D046911:Macromolecular Substances; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D000099200:Scaffold Protein ILK