Remodeling of dystrophin and sarcomeric Z-band occurs in pediatric cardiomyopathies

A unifying mechanism for force transmission defect

Matteo Vatta, Gianfranco Sinagra, Luca Brunelli, Georgine Faulkner

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 δ-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.

Original languageEnglish (US)
Pages (from-to)149-156
Number of pages8
JournalJournal of Cardiovascular Medicine
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2009

Fingerprint

Dystrophin
Cardiomyopathies
Pediatrics
Dilated Cardiomyopathy
Sarcomeres
Glycoproteins
Myocarditis
Sarcoglycans
Sarcolemma
Mutation
Cytoskeletal Proteins
Sequence Deletion
Heart Transplantation
Myocardium
Homeostasis
Heart Failure
Calcium

Keywords

  • Cardiomyopathy
  • Congestive heart failure
  • Dystrophin
  • Dystrophin-associated glycoprotein complex
  • Sarcomere

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Remodeling of dystrophin and sarcomeric Z-band occurs in pediatric cardiomyopathies : A unifying mechanism for force transmission defect. / Vatta, Matteo; Sinagra, Gianfranco; Brunelli, Luca; Faulkner, Georgine.

In: Journal of Cardiovascular Medicine, Vol. 10, No. 2, 01.02.2009, p. 149-156.

Research output: Contribution to journalArticle

@article{b142a13cdae040db9c8c80b48e2ef222,
title = "Remodeling of dystrophin and sarcomeric Z-band occurs in pediatric cardiomyopathies: A unifying mechanism for force transmission defect",
abstract = "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 δ-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.",
keywords = "Cardiomyopathy, Congestive heart failure, Dystrophin, Dystrophin-associated glycoprotein complex, Sarcomere",
author = "Matteo Vatta and Gianfranco Sinagra and Luca Brunelli and Georgine Faulkner",
year = "2009",
month = "2",
day = "1",
doi = "10.2459/JCM.0b013e328318954c",
language = "English (US)",
volume = "10",
pages = "149--156",
journal = "Journal of Cardiovascular Medicine",
issn = "1558-2027",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Remodeling of dystrophin and sarcomeric Z-band occurs in pediatric cardiomyopathies

T2 - A unifying mechanism for force transmission defect

AU - Vatta, Matteo

AU - Sinagra, Gianfranco

AU - Brunelli, Luca

AU - Faulkner, Georgine

PY - 2009/2/1

Y1 - 2009/2/1

N2 - 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 δ-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.

AB - 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 δ-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.

KW - Cardiomyopathy

KW - Congestive heart failure

KW - Dystrophin

KW - Dystrophin-associated glycoprotein complex

KW - Sarcomere

UR - http://www.scopus.com/inward/record.url?scp=65549160130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65549160130&partnerID=8YFLogxK

U2 - 10.2459/JCM.0b013e328318954c

DO - 10.2459/JCM.0b013e328318954c

M3 - Article

VL - 10

SP - 149

EP - 156

JO - Journal of Cardiovascular Medicine

JF - Journal of Cardiovascular Medicine

SN - 1558-2027

IS - 2

ER -