Abstract 231: Cardiac Myosin Binding Protein C Couples Cross-Bridge Cycling to Calcium Transients to Provide Normal Cardiac Function

Abstract

A 40-year old American has a 20% chance of developing heart failure (HF) in his/her lifetime. Although cross-bridge cycling forms the basis for contraction and relaxation of the heart, mechanisms that modulate cross-bridge cycling are not completely understood, nor are the alterations in these processes in HF. Cardiac myosin binding protein-C (MyBPC3) is a component of heart muscle that is believed to regulate cross-bridge cycling kinetics. We hypothesize that MyBPC3 tunes cross-bridge cycling to the [Ca2+]i transient to produce normal cardiac function, which we tested using our MyBPC3 knockout (KO) mouse. Echocardiography showed that MyBPC3(KO) hearts exhibited abbreviated aortic ejection durations (AED) and AED/(period between heart beats) ratio compared to WT. MyBPC3(KO) hearts also had smaller velocity-time integrals which indicate smaller stroke volumes as a result of abbreviated ejection. Brain natriuretic peptide expression level, heart weight/body weight, and lung weight/body weight were all increased in MyBPC3(KO) mice, consistent with HF. MyBPC3(KO) mice also exhibit increased 1-year mortality. We used simultaneous twitch force and intracellular calcium [Ca2+]i measurements on intact papillary muscles to evaluate the consequences of losing cross-bridge cycling regulation on force response to changing [Ca2+]i transients. MyBPC3 (KO) myocardium exhibited abbreviated contractions despite slower calcium transients and an inability to accelerate relaxation with respect to peak contraction. Therefore, loss of MyBPC3-mediated coupling of cross-bridge cycling to the [Ca2+]i transient was associated with contractile dysfunction and HF.