Transgenesis with a chimeric alpha-/beta-TM protein rescued the hypertrophic phenotype in FHC mice, resulting in normal morphology, improved cardiac function, and normal calcium sensitivity.
Does decreasing myofilament calcium sensitivity via a chimeric alpha-/beta-TM protein rescue the hypertrophic phenotype in a mouse model of familial hypertrophic cardiomyopathy?
Modifying contractile proteins to normalize calcium sensitivity can prevent the pathological and physiological effects of familial hypertrophic cardiomyopathy in a mouse model.
Familial hypertrophic cardiomyopathy (FHC) is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein alpha-tropomyosin (TM) at amino acid 180 (Glu180Gly). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity. The mice also develop severe cardiac hypertrophy, with death ensuing by 6 mo. In an attempt to normalize calcium sensitivity in the cardiomyofilaments of the hypertrophic mice, we generated a chimeric alpha-/beta-TM protein that decreases calcium sensitivity in transgenic mouse cardiac myofilaments. By mating mice from these two models together, we tested the hypothesis that an attenuation of myofilament calcium sensitivity would modulate the severe physiological and pathological consequences of the FHC mutation. These double-transgenic mice "rescue" the hypertrophic phenotype by exhibiting a normal morphology with no pathological abnormalities. Physiological analyses of these rescued mice show improved cardiac function and normal myofilament calcium sensitivity. These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease.
Jagatheesan et al. (Sat,) conducted a other in Familial hypertrophic cardiomyopathy (FHC). Chimeric alpha-/beta-TM protein transgenesis vs. FHC mice without the chimeric protein was evaluated on Hypertrophic phenotype, cardiac function, and myofilament calcium sensitivity. Transgenesis with a chimeric alpha-/beta-TM protein rescued the hypertrophic phenotype in FHC mice, resulting in normal morphology, improved cardiac function, and normal calcium sensitivity.