Distinct Patterns of Dystrophin Organization in Myocyte Sarcolemma and Transverse Tubules of Normal and Diseased Human Myocardium

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 (nϭ6) and failing hearts (idiopathic dilated cardiomyopathy, nϭ7, or ischemic heart disease, nϭ5). 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 significantly greater label on plasma membrane fractures overlying I-bands (I-band 4.1Ϯ0.3 gold particles/m; A-band 3.3Ϯ0.2 gold particles/m: meanϮSE, Pϭ0.02). 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 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 absence in skeletal muscle T-tubules, implies additional roles for dystrophin in membrane domain organization.

Structural remodelling of cardiomyocytes in the border zone of infarcted rabbit heart

“…The fact that they only occur in CMs in the border zone of infarcted myocardium and are always surrounded by fibrotic scar tissue suggests a mutual relation. Enlarged T-tubules running parallel to the longitudinal axis of the CM's and morphologically resembling the vacuoles seen in our study have been described in human left ventricular tissue from end-stage heart failure secondary to dilated cardiomyopathy [21]. Guinea pigs treated with an overload of volatile anaesthetics have been reported to show dilatations of the T-tubules [22], and dilatation of T-tubules through excessive activation of Na + -K + -ATPase from the sarcoplasmic side of the T-tubule membrane has been described in transected rat soleus muscle [23].…”

Myocardial Regeneration Therapy for Heart Failure

“…Recently, this adhesion system was reported to be important in heart muscle function as well, and mutations in these molecules may cause cardiomyopathies. 18 Our results of the strongest expression of both ␣-and ␤-dystroglycan in combined therapy group showed that cardiomyoplasty combined with HGF gene transfection induced sufficient expression levels of another important cell adhesion molecules for cardiomyocytes. Laminin is one of the bestdescribed molecules comprising the extracellular matrix proteins and is the main component of the basement membrane.…”

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na v 1.5 in Cardiomyocytes

“…4 The PDZ domain of syntrophin binds to the last 3 C-terminal residues of Na v 1.5 (Ser-Ile-Val, SIV), a PDZ-domain binding motif that mediates the interaction with dystrophin and other proteins of the DMC. 2 Interestingly, dystrophin has been shown to be absent from the intercalated discs of human 6 and rat 7 cardiac cells, suggesting that the Na v 1.5 channels present at these locations may interact with other regulatory or anchoring proteins.…”