Molecular Pathogenesis of Genetic and Inherited Diseases Deletion of Integrin-Linked Kinase from Skeletal Muscles of Mice Resembles Muscular Dystrophy Due to 71-Integrin Deficiency

Integrin-linked kinase (Ilk) is a serine/threonine ki-nase and an adaptor protein that links integrins to the actin cytoskeleton and to a number of signaling path-ways 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 extra-cellular matrix. Using the cre/lox system, we deleted Ilk from skeletal muscles of mice. The resulting mu-tants 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-re-lated proteins, including vinculin, paxillin, focal ad-hesion kinase, dystrophin, and the 71D-integrin subunits. Distal ends of mutant muscle fibers ap-peared irregular, and there was restructuring of the actin cytoskeleton. These findings resemble those seen in humans and mice lacking the 7-integrin sub-unit and suggest that Ilk may act as a cytoplasmic effector of 71-integrin in the pathogenesis of thes