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First published online 23 April 2008
doi: 10.1242/dev.015818

Development 135, 2043-2053 (2008)
Published by The Company of Biologists 2008
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Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle

Francesco J. Conti1, Amanda Felder2, Sue Monkley3, Martin Schwander1, Malcolm R. Wood4, Richard Lieber2, David Critchley3 and Ulrich Müller1,*

1 The Scripps Research Institute, Department of Cell Biology and Institute of Childhood and Neglected Disease, La Jolla, CA 92037, USA.
2 University of California and Veterans Administrative Centers, Department of Orthopaedics and Bioengineering, San Diego, CA 92037, USA.
3 University of Leicester, Department of Biochemistry, Leicester LE1 7RH, UK.
4 The Scripps Research Institute, Microscopy Core Facility, La Jolla, CA 92037, USA.

* Author for correspondence (e-mail: umueller{at}scripps.edu)

Accepted 31 March 2008

The development and function of skeletal muscle depend on molecules that connect the muscle fiber cytoskeleton to the extracellular matrix (ECM). β1 integrins are ECM receptors in skeletal muscle, and mutations that affect the {alpha}7β1 integrin cause myopathy in humans. In mice, β1 integrins control myoblast fusion, the assembly of the muscle fiber cytoskeleton, and the maintenance of myotendinous junctions (MTJs). The effector molecules that mediate β1 integrin functions in muscle are not known. Previous studies have shown that talin 1 controls the force-dependent assembly of integrin adhesion complexes and regulates the affinity of integrins for ligands. Here we show that talin 1 is essential in skeletal muscle for the maintenance of integrin attachment sites at MTJs. Mice with a skeletal muscle-specific ablation of the talin 1 gene suffer from a progressive myopathy. Surprisingly, myoblast fusion and the assembly of integrin-containing adhesion complexes at costameres and MTJs advance normally in the mutants. However, with progressive ageing, the muscle fiber cytoskeleton detaches from MTJs. Mechanical measurements on isolated muscles show defects in the ability of talin 1-deficient muscle to generate force. Collectively, our findings show that talin 1 is essential for providing mechanical stability to integrin-dependent adhesion complexes at MTJs, which is crucial for optimal force generation by skeletal muscle.

Key words: Integrin, Talin, Muscular dystrophy, Myopathy, Mouse






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