Abstract 13249: Muscle Enriched A-Type Lamin Interacting Protein (MLIP) Regulates Cardiac Metabolism, Growth and Function
Laminopathies are tissue-specific degenerative diseases primarily associated with the nuclear envelope protein A-type lamins. Clinical symptoms are varied and include: cardiovascular defects (dilated cardiomyopathy and atherosclerosis), muscular dystrophy (muscle wasting), lipodystrophy (fat wasting), neuropathy and progeria (premature aging). A major focus of current research is to discern the apparent conundrum of how a primary genetic defect in a ubiquitously expressed nuclear protein, A-type lamins, translates to tissue-specific effects. Our groups recent discovery of MLIP, a new gene that is most abundantly expressed in the heart, may account for the cardiovascular phenotypes observed in laminopathies. MLIP has no paralogous homologue suggesting no functional redundancy and it's biological function still remains elusive.
We have now established a MLIP mouse model in which MLIP hemizygous (+/-) null and MLIP homozygous (-/-) null mice develop dilated cardiomyopathy and lipodystrophy. Echocardiographic analysis of both 8 week old MLIP+/- and MLIP-/-mice develop enlarged hearts (heart to body weights MLIP+/+ 5.62mg/g vs MLIP+/- 10.73mg/g & MLIP -/- 11.03mg/g) that are functionally dilated with a significant increase in LVDD (+/+ 2.89mm; +/- 3.93mm; -/- 4.11mm) and reduction LVFS (+/+ 47%; +/- 31%; -/- 29%). Histological analysis of the hearts showed no overt phenotype other than an overall increase in the size of both MLIP+/- and MLIP-/- hearts. Like the LMNA null mouse, MLIP +/- and MLIP -/- mice have a 90% reduction in abdominal white adipose tissue. By 12 weeks of age both MLIP hemizygous and null mice cease to gain body weight, with the null mice starting to show a decline in body weight. FDG-PET analysis revealed a marked reduction in the in both the rate and absolute amount of glucose uptake by the hearts of MLIP +/- and MLIP -/-. Preliminary western analysis shows dysregulated Glut4 expression in both MLIP +/- and MLIP -/- hearts. Extensive metabolic and gene expression analysis of the MLIP mice are currently under investigation.
In conclusion, MLIP is a newly discovered lamin interacting protein that impacts genes involved in cardiac development, growth and function and provides a new signaling paradigm.
- © 2012 by American Heart Association, Inc.