Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure
While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that...
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creator | Lee, Hyoung-gon Chen, Qun Wolfram, Julie A Richardson, Sandy L Liner, Anna Siedlak, Sandra L Zhu, Xiongwei Ziats, Nicholas P Fujioka, Hisashi Felsher, Dean W Castellani, Rudy J Valencik, Maria L McDonald, John A Hoit, Brian D Lesnefsky, Edward J Smith, Mark A |
description | While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart. |
doi_str_mv | 10.1371/journal.pone.0007172 |
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To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0007172</identifier><identifier>PMID: 19779629</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging ; Alterations ; Alzheimer's disease ; Alzheimers disease ; Animals ; Apoptosis ; Biochemistry ; c-Myc protein ; Cardiomyocytes ; Cardiomyopathy ; Cardiomyopathy, Hypertrophic - metabolism ; Cardiovascular Disorders/Heart Failure ; Cardiovascular Disorders/Myopathies ; Cell activation ; Cell Cycle ; Cell Proliferation ; Complications ; Congestive heart failure ; Cyclin-dependent kinases ; Cytochrome ; Defects ; Dehydrogenases ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA replication ; Electron Transport ; Electron transport chain ; Female ; Fetuses ; Heart ; Heart attacks ; Heart failure ; Heart Failure - metabolism ; Hypertrophic cardiomyopathy ; Hypertrophy ; Kinases ; Major histocompatibility complex ; Medicine ; Mice ; Mice, Transgenic ; Mitochondria ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial DNA ; Models, Biological ; Multiple myeloma ; Myc protein ; Myocytes, Cardiac - cytology ; Pathology ; Physiology/Muscle and Connective Tissue ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc - metabolism ; Rodents ; Ventricle</subject><ispartof>PloS one, 2009-09, Vol.4 (9), p.e7172-e7172</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Lee et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-4f34ddd82e5ce17a6c70d60d9efa95ccfa47b7d687d390b2f5cd5af1ce8672423</citedby><cites>FETCH-LOGICAL-c729t-4f34ddd82e5ce17a6c70d60d9efa95ccfa47b7d687d390b2f5cd5af1ce8672423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747003/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747003/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2930,23873,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19779629$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kowaltowski, Alicia J.</contributor><creatorcontrib>Lee, Hyoung-gon</creatorcontrib><creatorcontrib>Chen, Qun</creatorcontrib><creatorcontrib>Wolfram, Julie A</creatorcontrib><creatorcontrib>Richardson, Sandy L</creatorcontrib><creatorcontrib>Liner, Anna</creatorcontrib><creatorcontrib>Siedlak, Sandra L</creatorcontrib><creatorcontrib>Zhu, Xiongwei</creatorcontrib><creatorcontrib>Ziats, Nicholas P</creatorcontrib><creatorcontrib>Fujioka, Hisashi</creatorcontrib><creatorcontrib>Felsher, Dean W</creatorcontrib><creatorcontrib>Castellani, Rudy J</creatorcontrib><creatorcontrib>Valencik, Maria L</creatorcontrib><creatorcontrib>McDonald, John A</creatorcontrib><creatorcontrib>Hoit, Brian D</creatorcontrib><creatorcontrib>Lesnefsky, Edward J</creatorcontrib><creatorcontrib>Smith, Mark A</creatorcontrib><title>Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.</description><subject>Aging</subject><subject>Alterations</subject><subject>Alzheimer's disease</subject><subject>Alzheimers disease</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>c-Myc protein</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cardiomyopathy, Hypertrophic - metabolism</subject><subject>Cardiovascular Disorders/Heart Failure</subject><subject>Cardiovascular Disorders/Myopathies</subject><subject>Cell activation</subject><subject>Cell Cycle</subject><subject>Cell Proliferation</subject><subject>Complications</subject><subject>Congestive heart failure</subject><subject>Cyclin-dependent kinases</subject><subject>Cytochrome</subject><subject>Defects</subject><subject>Dehydrogenases</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA replication</subject><subject>Electron Transport</subject><subject>Electron transport chain</subject><subject>Female</subject><subject>Fetuses</subject><subject>Heart</subject><subject>Heart attacks</subject><subject>Heart failure</subject><subject>Heart Failure - metabolism</subject><subject>Hypertrophic cardiomyopathy</subject><subject>Hypertrophy</subject><subject>Kinases</subject><subject>Major histocompatibility complex</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial DNA</subject><subject>Models, Biological</subject><subject>Multiple myeloma</subject><subject>Myc protein</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Pathology</subject><subject>Physiology/Muscle and Connective Tissue</subject><subject>Promoter Regions, Genetic</subject><subject>Proto-Oncogene Proteins c-myc - 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Hyoung-gon</au><au>Chen, Qun</au><au>Wolfram, Julie A</au><au>Richardson, Sandy L</au><au>Liner, Anna</au><au>Siedlak, Sandra L</au><au>Zhu, Xiongwei</au><au>Ziats, Nicholas P</au><au>Fujioka, Hisashi</au><au>Felsher, Dean W</au><au>Castellani, Rudy J</au><au>Valencik, Maria L</au><au>McDonald, John A</au><au>Hoit, Brian D</au><au>Lesnefsky, Edward J</au><au>Smith, Mark A</au><au>Kowaltowski, Alicia J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-09-25</date><risdate>2009</risdate><volume>4</volume><issue>9</issue><spage>e7172</spage><epage>e7172</epage><pages>e7172-e7172</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19779629</pmid><doi>10.1371/journal.pone.0007172</doi><tpages>e7172</tpages><oa>free_for_read</oa></addata></record> |
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issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1292103356 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Aging Alterations Alzheimer's disease Alzheimers disease Animals Apoptosis Biochemistry c-Myc protein Cardiomyocytes Cardiomyopathy Cardiomyopathy, Hypertrophic - metabolism Cardiovascular Disorders/Heart Failure Cardiovascular Disorders/Myopathies Cell activation Cell Cycle Cell Proliferation Complications Congestive heart failure Cyclin-dependent kinases Cytochrome Defects Dehydrogenases Deoxyribonucleic acid DNA DNA biosynthesis DNA replication Electron Transport Electron transport chain Female Fetuses Heart Heart attacks Heart failure Heart Failure - metabolism Hypertrophic cardiomyopathy Hypertrophy Kinases Major histocompatibility complex Medicine Mice Mice, Transgenic Mitochondria Mitochondria - metabolism Mitochondria - pathology Mitochondrial DNA Models, Biological Multiple myeloma Myc protein Myocytes, Cardiac - cytology Pathology Physiology/Muscle and Connective Tissue Promoter Regions, Genetic Proto-Oncogene Proteins c-myc - metabolism Rodents Ventricle |
title | Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-05T07%3A14%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cell%20cycle%20re-entry%20and%20mitochondrial%20defects%20in%20myc-mediated%20hypertrophic%20cardiomyopathy%20and%20heart%20failure&rft.jtitle=PloS%20one&rft.au=Lee,%20Hyoung-gon&rft.date=2009-09-25&rft.volume=4&rft.issue=9&rft.spage=e7172&rft.epage=e7172&rft.pages=e7172-e7172&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0007172&rft_dat=%3Cgale_plos_%3EA472860508%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1292103356&rft_id=info:pmid/19779629&rft_galeid=A472860508&rft_doaj_id=oai_doaj_org_article_9ab82388ceff4f3d8d97745aec42e465&rfr_iscdi=true |