Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy

Autores
Pereyra, Andrea Soledad; Hasek, Like Y.; Harris, Kate L.; Berman, Alycia G.; Damen, Frederick W.; Goergen, Craig J.; Ellis, Jessica M.
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2M/) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M/ mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60 –90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M/ hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M/ mice. Lysine acetylation was reduced by 50% in Cpt2M/ hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M/ hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M/ hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth.
Fil: Pereyra, Andrea Soledad. Purdue University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Hasek, Like Y.. Purdue University; Estados Unidos
Fil: Harris, Kate L.. Purdue University; Estados Unidos
Fil: Berman, Alycia G.. Purdue University; Estados Unidos
Fil: Damen, Frederick W.. Purdue University; Estados Unidos
Fil: Goergen, Craig J.. Purdue University; Estados Unidos
Fil: Ellis, Jessica M.. Purdue University; Estados Unidos
Materia
ACETYLATION
CARDIAC HYPERTROPHY
CARDIAC METABOLISM
FATTY ACID OXIDATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/100907

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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophyPereyra, Andrea SoledadHasek, Like Y.Harris, Kate L.Berman, Alycia G.Damen, Frederick W.Goergen, Craig J.Ellis, Jessica M.ACETYLATIONCARDIAC HYPERTROPHYCARDIAC METABOLISMFATTY ACID OXIDATIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2M/) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M/ mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60 –90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M/ hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M/ mice. Lysine acetylation was reduced by 50% in Cpt2M/ hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M/ hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M/ hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth.Fil: Pereyra, Andrea Soledad. Purdue University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hasek, Like Y.. Purdue University; Estados UnidosFil: Harris, Kate L.. Purdue University; Estados UnidosFil: Berman, Alycia G.. Purdue University; Estados UnidosFil: Damen, Frederick W.. Purdue University; Estados UnidosFil: Goergen, Craig J.. Purdue University; Estados UnidosFil: Ellis, Jessica M.. Purdue University; Estados UnidosAmerican Society for Biochemistry and Molecular Biology2017-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/100907Pereyra, Andrea Soledad; Hasek, Like Y.; Harris, Kate L.; Berman, Alycia G.; Damen, Frederick W.; et al.; Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 292; 45; 11-2017; 18443-184560021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.M117.800839info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M117.800839info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:15:42Zoai:ri.conicet.gov.ar:11336/100907instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:15:42.644CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
title Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
spellingShingle Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
Pereyra, Andrea Soledad
ACETYLATION
CARDIAC HYPERTROPHY
CARDIAC METABOLISM
FATTY ACID OXIDATION
title_short Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
title_full Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
title_fullStr Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
title_full_unstemmed Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
title_sort Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy
dc.creator.none.fl_str_mv Pereyra, Andrea Soledad
Hasek, Like Y.
Harris, Kate L.
Berman, Alycia G.
Damen, Frederick W.
Goergen, Craig J.
Ellis, Jessica M.
author Pereyra, Andrea Soledad
author_facet Pereyra, Andrea Soledad
Hasek, Like Y.
Harris, Kate L.
Berman, Alycia G.
Damen, Frederick W.
Goergen, Craig J.
Ellis, Jessica M.
author_role author
author2 Hasek, Like Y.
Harris, Kate L.
Berman, Alycia G.
Damen, Frederick W.
Goergen, Craig J.
Ellis, Jessica M.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ACETYLATION
CARDIAC HYPERTROPHY
CARDIAC METABOLISM
FATTY ACID OXIDATION
topic ACETYLATION
CARDIAC HYPERTROPHY
CARDIAC METABOLISM
FATTY ACID OXIDATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2M/) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M/ mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60 –90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M/ hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M/ mice. Lysine acetylation was reduced by 50% in Cpt2M/ hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M/ hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M/ hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth.
Fil: Pereyra, Andrea Soledad. Purdue University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Hasek, Like Y.. Purdue University; Estados Unidos
Fil: Harris, Kate L.. Purdue University; Estados Unidos
Fil: Berman, Alycia G.. Purdue University; Estados Unidos
Fil: Damen, Frederick W.. Purdue University; Estados Unidos
Fil: Goergen, Craig J.. Purdue University; Estados Unidos
Fil: Ellis, Jessica M.. Purdue University; Estados Unidos
description Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2M/) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M/ mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60 –90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M/ hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M/ mice. Lysine acetylation was reduced by 50% in Cpt2M/ hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M/ hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M/ hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth.
publishDate 2017
dc.date.none.fl_str_mv 2017-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/100907
Pereyra, Andrea Soledad; Hasek, Like Y.; Harris, Kate L.; Berman, Alycia G.; Damen, Frederick W.; et al.; Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 292; 45; 11-2017; 18443-18456
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/100907
identifier_str_mv Pereyra, Andrea Soledad; Hasek, Like Y.; Harris, Kate L.; Berman, Alycia G.; Damen, Frederick W.; et al.; Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 292; 45; 11-2017; 18443-18456
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.M117.800839
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M117.800839
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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