Expression of the beta (slow)-isoform of MHC in the adult mouse heart causes dominant-negative functional effects

alpha- and beta-myosin heavy chain (MHC), the two MHC isoforms expressed in the mammalian heart, differ quantitatively in their enzymatic activities. The MHC composition of the heart can change dramatically in response to num erous stimuli, leading to the hypothesis that changes in cardiac function c an be caused by myosin isoform shifts. However, this hypothesis has remaine d unproven because the stimuli used to generate these shifts are complex an d accompanied by many additional physiological changes, including alteratio ns in cardiac mass and geometry. Adult mouse ventricles normally express on ly alpha-MHC (the faster motor). To determine whether genetic alteration of the MHC isoform composition in the adult mouse heart would result in chang es in cardiac chamber mass and contractility, we established transgenic mou se lines that: express a Myc-tagged beta-MHC molecule (the slower motor) in adult ventricular tissue, one of which expreses 12% of its myosin as the t ransgene. There is no evidence of hypertrophy, induction of hypertrophic ma rkers, and no histopathology. Myofibrillar Ca2+-activated ATPase activity i s decreased by 23%, and Langendorff preparations demonstrate a significant 15% decrease in systolic function in transgenic hearts. These results sugge st that even small shifts in the myosin isoform composition of the myocardi um can result in physiologically significant changes in cardiac contractili ty and could be relevant to cardiovascular disease.