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Distinct patterns of dystrophin organization in myocyte sarcolemma and transverse tubules of normal and diseased human myocardium

Lookup NU author(s): Dr Michael Cullen

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Abstract

Background - Genetic mutations of dystrophin and associated glycoproteins underlie cell degeneration in several inherited cardiomyopathies, although the precise physiological role of these proteins remains under discussion. We studied the distribution of dystrophin in relation to the force-transducing vinculin-rich costameres in left ventricular cardiomyocytes from normal and failing human hearts to further elucidate the function of this protein complex. Methods and Results - Single- and double-label immunoconfocal microscopy and parallel high-resolution immunogold fracture-label electron microscopy were used to localize dystrophin and vinculin in human left ventricular myocytes from normal (n = 6) and failing hearts (idiopathic dilated cardiomyopathy, n = 7, or ischemic heart disease, n = 5). In control cardiomyocytes, dystrophin had a continuous distribution at the peripheral sarcolemma, with concentrated bands corresponding to the vinculin-rich costameres. Intracellular labeling extended along transverse (T) tubule membranes. Fracture-label confirmed this distribution, showing greater label on plasma membrane fractures overlying I- bands (I-bands 4.1 ± 0.3 gold particles/μm; A-band 3.3 ± 0.2 particles/μm: mean ± SE, P = 0.02. Hypertrophied myocytes from failing hearts showed maintenance of this surface distribution except in degenerating cells; there was a clear increase in intracellular dystrophin label reflecting T-tubule hypertrophy. Conclusions - Dystrophin partially colocalizes with costameric vinculin in normal and hypertrophied myocytes, a distribution lost in degenerating cells. This suggest a primarily mechanical role for dystrophin in maintenance of cell membrane integrity in normal and hypertrophied myocytes. The presence of dystrophin in the cardiac T-tubule membrane in contrast to its known absence in skeletal muscle T-tubule, implies additional roles for dystrophin in membrane domain organization.


Publication metadata

Author(s): Kaprielian RR, Stevenson S, Rothery SM, Cullen MJ, Severs NJ

Publication type: Article

Publication status: Published

Journal: Circulation

Year: 2000

Volume: 101

Issue: 22

Pages: 2586-2594

ISSN (print): 0009-7322

ISSN (electronic): 1524-4539

Publisher: Lippincott Williams & Wilkins

URL: http://circ.ahajournals.org/content/101/22/2586.short

PubMed id: 10840009


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