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.

• Authors: Jaclyn P Kerr, Andrew P Ziman, Amber L Mueller, Joaquin M Muriel, Emily Kleinhans-Welte, Jessica D Gumerson, Steven S Vogel, Christopher W Ward, Joseph A Roche, Robert J Bloch
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 51 Pg. 20831-6 (Dec 17 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 24302765 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Calcium Channels, L-Type
• Dysf protein, mouse
• Dysferlin
• Membrane Proteins
• Diltiazem

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Calcium Channels, L-Type (genetics, metabolism)
• Calcium Signaling
• Cell Membrane (metabolism, pathology)
• Diltiazem (pharmacology)
• Dysferlin
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Mutant Strains
• Muscle Contraction (drug effects, genetics)
• Muscle Fibers, Skeletal (metabolism, pathology)
• Muscular Dystrophies, Limb-Girdle (genetics, metabolism, pathology)
• Necrosis (genetics, metabolism, pathology)
• Stress, Physiological