Cardiac Myosin Binding Protein-C Phosphorylation in a β-Myosin Heavy Chain Background

Abstract

Background— Cardiac myosin binding protein-C (cMyBP-C) phosphorylation modulates cardiac contractility. When expressed in cMyBP-C–null (cMyBP-C ^(t/t) ) hearts, a cMyBP-C phosphomimetic (cMyBP-C ^AllP+ ) rescued cardiac dysfunction and protected the hearts from ischemia/reperfusion injury. However, cMyBP-C function may be dependent on the myosin isoform type. Because these replacements were performed in the mouse heart, which contains predominantly α-myosin heavy chain (α-MyHC), the applicability of the data to humans, whose cardiomyocytes contain predominantly β-MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a β-MyHC transgenic mouse heart in which >80% of the α-MyHC was replaced by β-MyHC, which is the predominant myosin isoform in human cardiac muscle. Methods and Results— To determine the effects of cMyBP-C phosphorylation in a β-MyHC background, transgenic mice expressing normal cMyBP-C (cMyBP-C ^WT ), nonphosphorylatable cMyBP-C (cMyBP-C ^{AllP −} ), or cMyBP-C ^AllP+ were bred into the β-MyHC background (β). These mice were then crossed into the cMyBP-C ^(t/t) background to ensure the absence of endogenous cMyBP-C. cMyBP-C ^(t/t)/β and cMyBP-C ^{AllP − :(t/t)/β} mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the β-MyHC background. cMyBP-C ^{AllP+:(t/t)/β} and cMyBP-C ^WT:(t/t)/β hearts showed no morbidity and mortality, and cMyBP-C ^{AllP+:(t/t)/β} hearts were significantly cardioprotected from ischemia/reperfusion injury. Conclusions— cMyBP-C phosphorylation is necessary for basal myocardial function in the β-MyHC background and can preserve function after ischemia/reperfusion injury. Our studies justify exploration of cMyBP-C phosphorylation as a therapeutic target in the human heart.