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 -myosin heavy chain (-MyHC), the applicability of the data to humans, whose cardiomyocytes contain predominantly -MyHC, is unclear. We determined the effect(s) of cMyBP-C phosphorylation in a -MyHC transgenic mouse heart in which >80% of the -MyHC was replaced by -MyHC, which is the predominant myosin isoform in human cardiac muscle.

Methods and Results—To determine the effects of cMyBP-C phosphorylation in a -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 -MyHC background (). These mice were then crossed into the cMyBP-C^(t/t) background to ensure the absence of endogenous cMyBP-C. cMyBP-C^(t/t)/ and cMyBP-C^AllP-:(t/t)/ mice died prematurely because of heart failure, confirming that cMyBP-C phosphorylation is essential in the -MyHC background. cMyBP-C^AllP+:(t/t)/ and cMyBP-C^WT:(t/t)/ hearts showed no morbidity and mortality, and cMyBP-C^AllP+:(t/t)/ hearts were significantly cardioprotected from ischemia/reperfusion injury.

Conclusions—cMyBP-C phosphorylation is necessary for basal myocardial function in the -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.