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

Background-Genetic mutations of dystrophin and associated glycoproteins und erlie 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 an d failing human hearts to further elucidate the function of this protein co mplex. 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 myocyte s 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 concentra ted bands corresponding to the vinculin-rich costameres. Intracellular labe ling extended along transverse (T) tubule membranes. Fracture-label confirm ed this distribution, showing significantly greater label on plasma membran e fractures overlying 1-bands (I-band 4.1 +/- 0.3 gold particles/mu m; A-ba nd 3.3 +/- 0.2 gold particles/mu m: mean +/- SE, P=0.02). Hypertrophied myo cytes from failing hearts showed maintenance of this surface distribution e xcept in degenerating cells; there was a clear increase in intracellular dy strophin label reflecting T-tubule hypertrophy. Conclusions-Dystrophin partially colocalizes with costameric vinculin in no rmal and hypertrophied myocytes, a distribution lost in degenerating cells. This suggests 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 a bsence in skeletal muscle T-tubules, implies additional roles for dystrophi n in membrane domain organization.