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

• Published in: The Journal of biological chemistry 2015-10, Vol.290 (44), p.26699-26714
• Main Authors: Cattin, Marie-Elodie, Wang, Jessica, Weldrick, Jonathan J., Roeske, Cassandra L., Mak, Esther, Thorn, Stephanie L., DaSilva, Jean N., Wang, Yibin, Lusis, Aldon J., Burgon, Patrick G.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Akt PKB; Animals; cardiac hypertrophy; Cardiomegaly - chemically induced; Cardiomegaly - diagnostic imaging; Cardiomegaly - genetics; Cardiomegaly - pathology; cardiomyopathy; cardiovascular disease; Carrier Proteins - genetics; Co-Repressor Proteins; Female; Gene Expression Regulation; Genome-Wide Association Study; heart failure; Heart Function Tests; Hemodynamics; homeostasis; Isoproterenol; Male; mammalian target of rapamycin (mTOR); Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Bases of Disease; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Phosphorylation; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Stress, Physiological; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Ultrasonography
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.678433

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. Background: MLIP (muscle enriched A-type lamin-interacting protein) is a unique protein of yet unknown function. Results: MLIP impacts cardiac activity of Akt/mTOR pathways and is associated with and required for precocious cardiac adaptation to stress. Conclusion: MLIP might be a new cardiac stress sensor. Significance: These findings provide the first insight into the role of MLIP in vivo.