A post-transcriptional compensatory pathway in heterozygous ventricular myosin light chain 2-deficient mice results in lack of gene dosage effect during normal cardiac growth or hypertrophy

Our previous study of homozygous mutants of the ventricular specific isofor m of myosin light chain 2 (mlc-2v) demonstrated that mlc-ev plays an essent ial role in murine heart development (Chen, J,, Kubalak, S, W,, Minamisawa, S,, Price, R, L,, Becker, K, D., Hickey, R,, Ross, J,, Jr,, and Chien, K, R, (1998) J. Biol. Chem. 273, 1252-1256), As gene dosage of some myofibrill ar proteins can affect muscle function, we have analyzed heterozygous mutan ts in depth. Ventricles of heterozygous mutants displayed a 50% reduction i n mlc-2v mRNA, yet expressed normal levels of protein both under basal cond itions and following induction of cardiac hypertrophy by aortic constrictio n. Heterozygous mutants exhibited cardiac function comparable to that of wi ld-type littermate controls both prior to and following aortic constriction . There were no significant differences in contractility and responses to c alcium between wild-type and heterozygous unloaded cardiomyocytes, We concl ude that heterozygous mutants show neither a molecular nor a physiological cardiac phenotype either at base line or following hypertrophic stimuli, Th ese results suggest that post-transcriptional compensatory mechanisms play a major role in maintaining the level of MLC-SV protein in murine hearts, I n addition, as our mlc-2v knockout mutants were created by a knock-in of Cr e recombinase into the endogenous mlc-ev locus, this study demonstrates tha t heterozygous mlc-ev cre knock-in mice are appropriate for ventricular spe cific gene targeting.