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Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane.

ABSTRACT: Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin's association with calcium (Ca(2+)) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal muscle fibers. Following experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive functional and structural disruption of the t-tubules that is ameliorated by reducing external [Ca(2+)] or blocking L-type Ca(2+) channels with diltiazem. Furthermore, we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric contraction-induced t-tubule damage, inflammation, and necrosis, which resulted in a concomitant increase in postinjury functional recovery. Our discovery of dysferlin as a t-tubule protein that stabilizes stress-induced Ca(2+) signaling offers a therapeutic avenue for limb girdle muscular dystrophy 2B and Miyoshi myopathy patients.

SUBMITTER: Kerr JP

PROVIDER: S-EPMC3870721 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane.

Kerr Jaclyn P JP Ziman Andrew P AP Mueller Amber L AL Muriel Joaquin M JM Kleinhans-Welte Emily E Gumerson Jessica D JD Vogel Steven S SS Ward Christopher W CW Roche Joseph A JA Bloch Robert J RJ

Proceedings of the National Academy of Sciences of the United States of America 20131203 51

Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin's association with calcium (Ca(2+)) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal mu ...[more]

PMID: 24302765

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Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane.

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Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane.

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