Phenotypic deficits in mice expressing a myosin binding protein C lacking the titin and myosin binding domains.

The majority of familial hypertrophic cardiomyopathy patients carrying a mutation in the cardiac myosin binding protein C gene show low penetrance, late onset of the disease and a relatively benign phenotype. Sudden death in these patients, if it occurs, usually takes place after the fifth or sixth decade of life and can be precipitated by stress. Previously, we prepared mice carrying a mutated MyBP-C lacking both the titin and myosin binding sites at the carboxyl terminus. This mutation is found in some familial hypertrophic cardiomyopathy patients and the mice develop some symptoms that are consistent with the disease. In the present study, we wished to determine the response of these animals to various forms of cardiovascular stress. Consistent with the human disease presentation, only a mild cardiac hypertrophy was detected in unstressed animals. Although there are no complementary human data with which to compare the mice, molecular signs of stress were apparent in the animals, as increased levels of the intermediate filament protein, desmin and the chaperone protein, alpha-B-crystallin, were present in the hearts. To determine whether the animals were sensitive to stress, they were subjected to sub-maximal treadmill exercise or to chronic isoproterenol infusion. The affected mice were significantly compromised in their exercise capacity and showed an impaired response during isoproterenol infusion. Increased mortality was observed during the exercise regimen, with some animals experiencing sudden death. We conclude that the mouse model recapitulates some of the known aspects of the human disease, particularly its late onset and benign phenotype. However, cardiac stress can lead to severe bradycardia and death. Copyright 2001 Academic Press.