Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes adverse cardiac remodeling
The mechanistic target of rapamycin (mTOR) promotes pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective; however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased...
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creator | Górska, Agnieszka A Sandmann, Clara Riechert, Eva Hofmann, Christoph Malovrh, Ellen Varma, Eshita Kmietczyk, Vivien Ölschläger, Julie Jürgensen, Lonny Kamuf-Schenk, Verena Stroh, Claudia Furkel, Jennifer Konstandin, Mathias H Sticht, Carsten Boileau, Etienne Dieterich, Christoph Frey, Norbert Katus, Hugo A Doroudgar, Shirin Völkers, Mirko |
description | The mechanistic target of rapamycin (mTOR) promotes pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective; however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is unknown. We performed cardiomyocyte genome-wide sequencing to define mTOR-dependent gene expression control at the level of mRNA translation. We identify the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we show that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value against pathological cardiac remodeling.
SYNOPSIS
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.
Cand2 is translationally upregulated during pathological stress in cardiac myocytes.
Cand2 expression depends on the activity of mTORC1.
Cand2 promotes the expression of G-protein coupled receptor 5 (Grk5), which in turn links to myocyte enhancer factor 2 (MEF2)-driven transcription of cardiac hypertophy genes.
Graphical Abstract
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy. |
doi_str_mv | 10.15252/embr.202052170 |
format | Article |
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SYNOPSIS
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.
Cand2 is translationally upregulated during pathological stress in cardiac myocytes.
Cand2 expression depends on the activity of mTORC1.
Cand2 promotes the expression of G-protein coupled receptor 5 (Grk5), which in turn links to myocyte enhancer factor 2 (MEF2)-driven transcription of cardiac hypertophy genes.
Graphical Abstract
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.</description><identifier>ISSN: 1469-221X</identifier><identifier>EISSN: 1469-3178</identifier><identifier>DOI: 10.15252/embr.202052170</identifier><identifier>PMID: 34605609</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Cand2 ; cardiac ; Cardiomyocytes ; Coronary artery disease ; Cullin ; EMBO24 ; Gene deletion ; Gene expression ; Gene sequencing ; Genes ; Genomes ; Heart diseases ; Humans ; Hypertrophy ; Mechanistic Target of Rapamycin Complex 1 - genetics ; Mechanistic Target of Rapamycin Complex 1 - metabolism ; mTOR ; Muscle Proteins ; Muscles ; Myocardium ; Myocardium - metabolism ; Myocyte enhancer factor 2 ; Myocytes ; Myocytes, Cardiac - metabolism ; Proteins ; Rapamycin ; Signal Transduction ; TOR protein ; Transcription Factors ; Translation ; Up-Regulation ; Ventricular Remodeling - genetics</subject><ispartof>EMBO reports, 2021-12, Vol.22 (12), p.e52170-n/a</ispartof><rights>The Author(s) 2021</rights><rights>2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license</rights><rights>2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5130-3fbc17a92951f7e32d828e59061d19a75d31d02fe9a087a2c4cad4af21149913</citedby><cites>FETCH-LOGICAL-c5130-3fbc17a92951f7e32d828e59061d19a75d31d02fe9a087a2c4cad4af21149913</cites><orcidid>0000-0002-9737-3406 ; 0000-0003-4667-6690 ; 0000-0002-1964-4098 ; 0000-0001-9355-0973 ; 0000-0001-9115-8628 ; 0000-0003-4876-7860 ; 0000-0003-0911-6125 ; 0000-0002-4728-4077 ; 0000-0001-9468-6311 ; 0000-0002-3389-6582 ; 0000-0003-2344-1856</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647021/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647021/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,41120,42189,45574,45575,46409,46833,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34605609$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Górska, Agnieszka A</creatorcontrib><creatorcontrib>Sandmann, Clara</creatorcontrib><creatorcontrib>Riechert, Eva</creatorcontrib><creatorcontrib>Hofmann, Christoph</creatorcontrib><creatorcontrib>Malovrh, Ellen</creatorcontrib><creatorcontrib>Varma, Eshita</creatorcontrib><creatorcontrib>Kmietczyk, Vivien</creatorcontrib><creatorcontrib>Ölschläger, Julie</creatorcontrib><creatorcontrib>Jürgensen, Lonny</creatorcontrib><creatorcontrib>Kamuf-Schenk, Verena</creatorcontrib><creatorcontrib>Stroh, Claudia</creatorcontrib><creatorcontrib>Furkel, Jennifer</creatorcontrib><creatorcontrib>Konstandin, Mathias H</creatorcontrib><creatorcontrib>Sticht, Carsten</creatorcontrib><creatorcontrib>Boileau, Etienne</creatorcontrib><creatorcontrib>Dieterich, Christoph</creatorcontrib><creatorcontrib>Frey, Norbert</creatorcontrib><creatorcontrib>Katus, Hugo A</creatorcontrib><creatorcontrib>Doroudgar, Shirin</creatorcontrib><creatorcontrib>Völkers, Mirko</creatorcontrib><title>Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes adverse cardiac remodeling</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><addtitle>EMBO Rep</addtitle><description>The mechanistic target of rapamycin (mTOR) promotes pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective; however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is unknown. We performed cardiomyocyte genome-wide sequencing to define mTOR-dependent gene expression control at the level of mRNA translation. We identify the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we show that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value against pathological cardiac remodeling.
SYNOPSIS
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.
Cand2 is translationally upregulated during pathological stress in cardiac myocytes.
Cand2 expression depends on the activity of mTORC1.
Cand2 promotes the expression of G-protein coupled receptor 5 (Grk5), which in turn links to myocyte enhancer factor 2 (MEF2)-driven transcription of cardiac hypertophy genes.
Graphical Abstract
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.</description><subject>Cand2</subject><subject>cardiac</subject><subject>Cardiomyocytes</subject><subject>Coronary artery disease</subject><subject>Cullin</subject><subject>EMBO24</subject><subject>Gene deletion</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Genomes</subject><subject>Heart diseases</subject><subject>Humans</subject><subject>Hypertrophy</subject><subject>Mechanistic Target of Rapamycin Complex 1 - genetics</subject><subject>Mechanistic Target of Rapamycin Complex 1 - metabolism</subject><subject>mTOR</subject><subject>Muscle Proteins</subject><subject>Muscles</subject><subject>Myocardium</subject><subject>Myocardium - metabolism</subject><subject>Myocyte enhancer factor 2</subject><subject>Myocytes</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Signal Transduction</subject><subject>TOR protein</subject><subject>Transcription Factors</subject><subject>Translation</subject><subject>Up-Regulation</subject><subject>Ventricular Remodeling - 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genetics</topic><topic>Mechanistic Target of Rapamycin Complex 1 - metabolism</topic><topic>mTOR</topic><topic>Muscle Proteins</topic><topic>Muscles</topic><topic>Myocardium</topic><topic>Myocardium - metabolism</topic><topic>Myocyte enhancer factor 2</topic><topic>Myocytes</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Proteins</topic><topic>Rapamycin</topic><topic>Signal Transduction</topic><topic>TOR protein</topic><topic>Transcription Factors</topic><topic>Translation</topic><topic>Up-Regulation</topic><topic>Ventricular Remodeling - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Górska, Agnieszka A</creatorcontrib><creatorcontrib>Sandmann, Clara</creatorcontrib><creatorcontrib>Riechert, Eva</creatorcontrib><creatorcontrib>Hofmann, Christoph</creatorcontrib><creatorcontrib>Malovrh, Ellen</creatorcontrib><creatorcontrib>Varma, Eshita</creatorcontrib><creatorcontrib>Kmietczyk, Vivien</creatorcontrib><creatorcontrib>Ölschläger, Julie</creatorcontrib><creatorcontrib>Jürgensen, Lonny</creatorcontrib><creatorcontrib>Kamuf-Schenk, Verena</creatorcontrib><creatorcontrib>Stroh, Claudia</creatorcontrib><creatorcontrib>Furkel, Jennifer</creatorcontrib><creatorcontrib>Konstandin, Mathias H</creatorcontrib><creatorcontrib>Sticht, Carsten</creatorcontrib><creatorcontrib>Boileau, Etienne</creatorcontrib><creatorcontrib>Dieterich, Christoph</creatorcontrib><creatorcontrib>Frey, Norbert</creatorcontrib><creatorcontrib>Katus, Hugo A</creatorcontrib><creatorcontrib>Doroudgar, Shirin</creatorcontrib><creatorcontrib>Völkers, Mirko</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Górska, Agnieszka A</au><au>Sandmann, Clara</au><au>Riechert, Eva</au><au>Hofmann, Christoph</au><au>Malovrh, Ellen</au><au>Varma, Eshita</au><au>Kmietczyk, Vivien</au><au>Ölschläger, Julie</au><au>Jürgensen, Lonny</au><au>Kamuf-Schenk, Verena</au><au>Stroh, Claudia</au><au>Furkel, Jennifer</au><au>Konstandin, Mathias H</au><au>Sticht, Carsten</au><au>Boileau, Etienne</au><au>Dieterich, Christoph</au><au>Frey, Norbert</au><au>Katus, Hugo A</au><au>Doroudgar, Shirin</au><au>Völkers, Mirko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes adverse cardiac remodeling</atitle><jtitle>EMBO reports</jtitle><stitle>EMBO Rep</stitle><addtitle>EMBO Rep</addtitle><date>2021-12-06</date><risdate>2021</risdate><volume>22</volume><issue>12</issue><spage>e52170</spage><epage>n/a</epage><pages>e52170-n/a</pages><issn>1469-221X</issn><eissn>1469-3178</eissn><abstract>The mechanistic target of rapamycin (mTOR) promotes pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective; however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is unknown. We performed cardiomyocyte genome-wide sequencing to define mTOR-dependent gene expression control at the level of mRNA translation. We identify the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we show that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value against pathological cardiac remodeling.
SYNOPSIS
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.
Cand2 is translationally upregulated during pathological stress in cardiac myocytes.
Cand2 expression depends on the activity of mTORC1.
Cand2 promotes the expression of G-protein coupled receptor 5 (Grk5), which in turn links to myocyte enhancer factor 2 (MEF2)-driven transcription of cardiac hypertophy genes.
Graphical Abstract
Genome-wide translational profiling identifies mTORC1-dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle-specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34605609</pmid><doi>10.15252/embr.202052170</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-9737-3406</orcidid><orcidid>https://orcid.org/0000-0003-4667-6690</orcidid><orcidid>https://orcid.org/0000-0002-1964-4098</orcidid><orcidid>https://orcid.org/0000-0001-9355-0973</orcidid><orcidid>https://orcid.org/0000-0001-9115-8628</orcidid><orcidid>https://orcid.org/0000-0003-4876-7860</orcidid><orcidid>https://orcid.org/0000-0003-0911-6125</orcidid><orcidid>https://orcid.org/0000-0002-4728-4077</orcidid><orcidid>https://orcid.org/0000-0001-9468-6311</orcidid><orcidid>https://orcid.org/0000-0002-3389-6582</orcidid><orcidid>https://orcid.org/0000-0003-2344-1856</orcidid><oa>free_for_read</oa></addata></record> |
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source | Wiley Online Library - AutoHoldings Journals; MEDLINE; Springer Nature OA Free Journals; EZB-FREE-00999 freely available EZB journals; Wiley Online Library (Open Access Collection); PubMed Central |
subjects | Cand2 cardiac Cardiomyocytes Coronary artery disease Cullin EMBO24 Gene deletion Gene expression Gene sequencing Genes Genomes Heart diseases Humans Hypertrophy Mechanistic Target of Rapamycin Complex 1 - genetics Mechanistic Target of Rapamycin Complex 1 - metabolism mTOR Muscle Proteins Muscles Myocardium Myocardium - metabolism Myocyte enhancer factor 2 Myocytes Myocytes, Cardiac - metabolism Proteins Rapamycin Signal Transduction TOR protein Transcription Factors Translation Up-Regulation Ventricular Remodeling - genetics |
title | Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes adverse cardiac remodeling |
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