Cardiac myosin binding protein-C phosphorylation in a β-myosin heavy chain background

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^AIlp+) 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 predorninantly 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.