Remodeling of dystrophin and sarcomeric Z-band occurs in pediatric cardiomyopathies: a unifying mechanism for force transmission defect.

BACKGROUND: Cardiomyopathies (CMPs) lead to associated systolic dysfunction and are the major causes of congestive heart failure and a leading cause for heart transplantation. Although the precise mechanism leading to systolic dysfunction is still elusive, chronic mechanical loading, along with altered calcium (Ca) cellular homeostasis, is believed to impair force transmission and induce cardiac morphological and structural changes, namely cardiac remodeling. Interestingly, dystrophin remodeling has been previously reported to occur in adults with end-stage CMP irrespective of the underlying cause.

METHODS: In order to determine the structural culprit associated with pediatric dilated cardiomyopathy (DCM) due to various causes, we investigated the structural continuum connecting dystrophin and the dystrophin-associated glycoprotein complex to the contractile apparatus in heart samples from four children with idiopathic dilated CMP: one with myocarditis, one sporadic DCM child previously identified with a delta-sarcoglycan deletion mutation, and one child with X-linked CMP with a reported splicing site mutation in the dystrophin-coded DYS gene.

RESULTS: Immunohistochemical analysis of cytoskeletal proteins connecting the dystrophin-associated glycoprotein complex to the sarcomere identified that myocarditis, idiopathic, and genetic-based DCM are characterized by disruption of the dystrophin connection to the sarcomere and perturbation of the Z-band.

CONCLUSION: Our data suggest that both dystrophin remodeling and sarcomeric Z-band/disk derangements may occur in the myocardium of children with DCM irrespective of the cause. This suggests that genetic mutations in the dystrophin-associated glycoprotein complex or any of its partners could result in sarcomere-sarcolemma connection alteration and associated Z-band disturbance, thus leading to force transmission dysfunction.