Deletion of integrin-linked kinase from skeletal muscles of mice resembles muscular dystrophy due to alpha 7 beta 1-integrin deficiency.
Integrin-linked kinase (Ilk) is a serine/threonine kinase and an adaptor protein that links integrins to the actin cytoskeleton and to a number of signaling pathways involved in integrin action. We hypothesized that Ilk may act as an important effector of integrins in skeletal muscle, where these receptors provide a critical link between the sarcolemma and the extracellular matrix. Using the cre/lox system, we deleted Ilk from skeletal muscles of mice. The resulting mutants developed a progressive muscular dystrophy with multiple degenerating and regenerating muscle fibers, increased central nuclei, and endomysial fibrosis. These defects were widespread but were most severe near myofascial junctions where Ilk mutants showed displacement of focal adhesion-related proteins, including vinculin, paxillin, focal adhesion kinase, dystrophin, and the alpha 7 beta 1D-integrin subunits. Distal ends of mutant muscle fibers appeared irregular, and there was restructuring of the actin cytoskeleton. These findings resemble those seen in humans and mice lacking the alpha 7-integrin subunit and suggest that Ilk may act as a cytoplasmic effector of alpha 7 beta1-integrin in the pathogenesis of these deficiencies.
Gheyara
Ania L
AL
Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA.
Vallejo-Illarramendi
Ainara
A
Zang
Keling
K
Mei
Lin
L
St-Arnaud
Rene
R
Dedhar
Shoukat
S
Reichardt
Louis F
LF
D000818:Animals; D022001:Focal Adhesions; D016023:Integrins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology* / Q000502:physiology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D000099200:Scaffold Protein ILK
D016023:Integrins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C082908:integrin alpha7beta1