Published online before print November 30, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070555

Accepted for publication August 23, 2007.

Article

Deletion of Integrin-Linked Kinase from Skeletal Muscles of Mice Resembles Muscular Dystrophy Due to 71-Integrin Deficiency

Ania L. Gheyara^*, Ainara Vallejo-Illarramendi, Keling Zang, Lin Mei, Rene St.-Arnaud, Shoukat Dedhar^¶, and Louis F. Reichardt^@

From the Departments of Pathology* and Physiology, University of California, San Francisco, California; the Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, Medical College of Georgia, Augusta, Georgia; the Shriners Hospital and McGill University, Montreal, Quebec, Canada; and the Department of Biochemistry and Molecular Biology,^¶ University of British Columbia, Vancouver, British Columbia, Canada

^@ To whom correspondence should be addressed. E-mail: louis.Reichardt{at}ucsf.edu.

	Abstract

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 71D-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 7-integrin subunit and suggest that Ilk may act as a cytoplasmic effector of 71-integrin in the pathogenesis of these deficiencies.

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