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First published online 30 October 2007
doi: 10.1242/jcs.009241

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Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization

Michele R. Stone^1,*,, Andrea O'Neill^1,*, Richard M. Lovering^1,*, John Strong¹, Wendy G. Resneck¹, Patrick W. Reed¹, Diana M. Toivola^2,3, Jeanine A. Ursitti⁴, M. Bishr Omary^2,3 and Robert J. Bloch^1,

¹ Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
² Department of Medicine, Palo Alto VA Medical Center, 3801 Miranda Avenue, Mail code 154J, Palo Alto, CA 94304, USA
³ Stanford University Digestive Disease Center, 300 Pasteur Drive, Stanford, CA 94305, USA
⁴ Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA

Author for correspondence (e-mail: rbloch{at}umaryland.edu)

Accepted 10 September 2007

Intermediate filaments, composed of desmin and of keratins, play important roles in linking contractile elements to each other and to the sarcolemma in striated muscle. We examined the contractile properties and morphology of fast-twitch skeletal muscle from mice lacking keratin 19. Tibialis anterior muscles of keratin-19-null mice showed a small but significant decrease in mean fiber diameter and in the specific force of tetanic contraction, as well as increased plasma creatine kinase levels. Costameres at the sarcolemma of keratin-19-null muscle, visualized with antibodies against spectrin or dystrophin, were disrupted and the sarcolemma was separated from adjacent myofibrils by a large gap in which mitochondria accumulated. The costameric dystrophin-dystroglycan complex, which co-purified with -actin, keratin 8 and keratin 19 from striated muscles of wild-type mice, co-purified with -actin but not keratin 8 in the mutant. Our results suggest that keratin 19 in fast-twitch skeletal muscle helps organize costameres and links them to the contractile apparatus, and that the absence of keratin 19 disrupts these structures, resulting in loss of contractile force, altered distribution of mitochondria and mild myopathy. This is the first demonstration of a mammalian phenotype associated with a genetic perturbation of keratin 19.

Key words: Costamere, Sarcomere, Desmin, Dystrophin, Sarcolemma, Spectrin

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