Abstract 205: Mlip is a New Integrator of Physiological Stress Required For Proper Cardiac Adaptation
Aging and diseases are generally a result of the inability of tissues to properly adapt to stress. The heart is particularly vulnerable to disequilibrium in homeostasis as its regenerative capacities are limited. Many molecular players have been identified as cardiac gate-keepers and integrators of stress, all essential to preserve cardiac function. However, the molecular basis of the relationship between aging and the pathogenesis of cardiac dysfunction remains poorly understood. Muscle enriched A-type lamin interacting protein (MLIP) is a unique mammalian protein of unknown function that was recently identified through its interaction with A-type lamins in the heart and as a modulator of cardiac hypertrophy in vitro. Here we report that young Mlip deficient mice develop dilated cardiomyopathy, manifested by an increase in heart mass with reduced cardiac function. Through global gene expression profiling of the Mlip deficient hearts, we identified a deregulation in mTOR signalling, a key stress sensing canonical pathway. Analysis of mTOR regulatory proteins (AMPK and AKT) revealed hyperactivation of the mTOR pathway and a deregulated integration of these two stress/nutrient sensors. These data support the notion that Mlip deficient hearts have impaired cardiac adaptation due to deregulated mTOR activity resulting in maladaptive remodeling, and the development of dilated cardiomyopathy. These results are further supported by a genetic association between Mlip and early response to pro-hypertrophic stimulus. Collectively, these results demonstrate that Mlip is required for normal integration of physiological stress (postnatal cardiac growth, isoproterenol-induced hypertrophy) through the regulation of the AMPK/Akt/mTOR pathway to maintain cardiac homeostasis in the adult heart.
Author Disclosures: M. Cattin: None. J. Wang: None. C. Roeske: None. E. Mak: None. S.L. Thorn: None. J.N. DaSilva: None. Y. Wang: None. A.J. Lusis: None. P.G. Burgon: None.
- © 2015 by American Heart Association, Inc.