Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere

Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca2+ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/−) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/− hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/− hearts displayed decreased cross-bridge stiffness at half-maximal Ca2+ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca2+ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/− and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/− hearts displayed abnormal sarcomere shortening but unchanged Ca2+ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/− hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/− mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca2+ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/− mice could increase their susceptibility to cardiac dysfunction and arrhythmia.