MYOSTATIN OVEREXPRESSION REDUCES HEART MASS IN THE MOUSE BUT DOES NOT AFFECT CARDIAC FUNCTION.

Abstract

Myostatin (Mst) is an endogenous negative regulator of skeletal muscle mass in humans, rodents, cattle, and other animals. Mst has been found at low levels in normal sheep and cattle heart tissue, which increase considerably after infarction. Genetic blockade of Mst expression increases cardiomyocyte growth, but this also occurs in heart hypertrophy, possibly as a compensatory mechanism. We aimed here to compare cardiac size and function in young (7 weeks old) transgenic mice overexpressing Mst in the heart (Mst TG) under a muscle specific creatine kinase (MCK) promoter that is activated in both cardiac and skeletal muscle versus the Mst knockout (Mst [−/−]) mice, and to determine whether Mst modulation of cardiomyocyte growth occurs at the level of cell proliferation. Cardiac angiography revealed that the left ventricular ejection fraction (LVEF) did not differ significantly between the Mst TG and the Mst (−/−) mice compared with their respective wild-type strains. This occurred despite a significant decrease in whole heart and left ventricular size in Mst TG mice as opposed to the respective increase observed in Mst (−/−) animals, associated with the expected higher or nil expression of cardiac Mst, respectively, estimated by RT/PCR and Western blot. Mst and its receptor, the ActRIIb, were found to be expressed in H9c2 cardiomyocyte cell cultures by RT/PCR, and transfections with plasmids expressing Mst full-length protein under muscle-specific MCK (pMCK/Mst), or general CMV (pCMV/Mst) promoters, enhanced p21 and reduced cdk2 expression, assessed by Western blot. This translated into a significant decrease in cell proliferation with increasing concentrations of Mst recombinant protein, as determined by the formazan assay, whereas anti-Mst antibody exerted the opposite effects. Transfection of H9c2 cells with the pMCK/Mst, or pCMV/Mst plasmids, inhibited cell proliferation more effectively. In conclusion, Mst does not affect directly global cardiac systolic function in TG mice overexpressing or lacking the active protein, despite Mst9s inhibitory effects on cardiac mass and cardiomyocyte proliferation.