Hdl Handle:
http://hdl.handle.net/10675.2/701
Title:
Ex Vivo Stretch Reveals Altered Mechanical Properties of Isolated Dystrophin-Deficient Hearts
Authors:
Barnabei, Matthew S.; Metzger, Joseph M.
Abstract:
Duchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from b-sarcoglycan-null and laminin-a2 mutant mice, but not in dysferlin-null mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.
Citation:
PLoS One. 2012 Mar 9; 7(3):e32880
Issue Date:
9-Mar-2012
URI:
http://hdl.handle.net/10675.2/701
DOI:
10.1371/journal.pone.0032880
PubMed ID:
22427904
PubMed Central ID:
PMC3298453
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Cellular Biology and Anatomy: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorBarnabei, Matthew S.en_US
dc.contributor.authorMetzger, Joseph M.en_US
dc.date.accessioned2012-10-26T16:29:36Z-
dc.date.available2012-10-26T16:29:36Z-
dc.date.issued2012-03-9en_US
dc.identifier.citationPLoS One. 2012 Mar 9; 7(3):e32880en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22427904en_US
dc.identifier.doi10.1371/journal.pone.0032880en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/701-
dc.description.abstractDuchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from b-sarcoglycan-null and laminin-a2 mutant mice, but not in dysferlin-null mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.en_US
dc.rightsBarnabei, Metzger. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectGeneticsen_US
dc.subjectHuman Geneticsen_US
dc.subjectX-Linkeden_US
dc.subjectModel Organismsen_US
dc.subjectAnimal Modelsen_US
dc.subjectMedicineen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectNeurologyen_US
dc.subject.meshAnalysis of Varianceen_US
dc.subject.meshAnimalsen_US
dc.subject.meshComplianceen_US
dc.subject.meshDystrophinen_US
dc.subject.meshFluorescent Antibody Techniqueen_US
dc.subject.meshL-Lactate Dehydrogenaseen_US
dc.subject.meshLamininen_US
dc.subject.meshMembrane Proteinsen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred mdxen_US
dc.subject.meshMicroscopy, Confocalen_US
dc.subject.meshModels, Biologicalen_US
dc.subject.meshMuscular Dystrophy, Duchenneen_US
dc.subject.meshMyocytes, Cardiacen_US
dc.subject.meshPhysical Stimulationen_US
dc.subject.meshSarcoglycansen_US
dc.subject.meshSarcomeresen_US
dc.subject.meshStress, Mechanicalen_US
dc.subject.meshVentricular Function, Leften_US
dc.titleEx Vivo Stretch Reveals Altered Mechanical Properties of Isolated Dystrophin-Deficient Heartsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3298453en_US
dc.contributor.corporatenameDepartment of Cellular Biology and Anatomy-
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