title: Deletion of MLIP (muscle-enriched A-type lamin-interacting protein) leads to cardiac hyperactivation of Akt/mammalian target of rapamycin (mTOR) and impaired cardiac adaptation.
abstract: Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip(-/-) mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip(-/-) hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada.
authors.forename: Marie-Elodie
authors.initials: ME
authors.lastname: Cattin
authors.affiliation: the Departments of Medicine.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada, the Departments of Cellular and Molecular Medicine, and Medicine (Cardiology), Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Weldrick
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Roeske
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Mak
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada, the Departments of Cellular and Molecular Medicine, and Medicine (Cardiology), Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Thorn
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada, the Departments of Cellular and Molecular Medicine, and Medicine (Cardiology), Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: Jean N
authors.initials: JN
authors.lastname: DaSilva
authors.affiliation: Anesthesiology, Physiology & Medicine, and.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Microbiology, Immunology and Molecular Genetics, Human Genetics & Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, and.
authors.forename: Aldon J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada, the Departments of Cellular and Molecular Medicine, and Medicine (Cardiology), Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada pburgon@ottawaheart.ca.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Burgon
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D056970:Co-Repressor Proteins; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006334:Heart Function Tests; D006439:Hemodynamics; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C559899:MLIP protein, mouse; D009687:Nuclear Proteins; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D007545:Isoproterenol
keywords: Akt PKB; cardiac hypertrophy; cardiomyopathy; cardiovascular disease; heart failure; homeostasis; mammalian target of rapamycin (mTOR)