Phosphorylation and function of cardiac myosin binding protein-C in health and disease

Abstract

During the past 5 years there has been an increasing body of literature describing the roles cardiac myosin binding protein C (cMyBP-C) phosphorylation play in regulating cardiac function and heart failure. cMyBP-C is a sarcomeric thick filament protein that interacts with titin, myosin and actin to regulate sarcomeric assembly, structure and function. Elucidating the function of cMyBP-C is clinically important because mutations in this protein have been linked to cardiomyopathy in more than sixty million people worldwide. One function of cMyBP-C is to regulate cross-bridge formation through dynamic phosphorylation by protein kinase A, protein kinase C and Ca²⁺-calmodulin-activated kinase II, suggesting that cMyBP-C phosphorylation serves as a highly coordinated point of contractile regulation. Moreover, dephosphorylation of cMyBP-C, which accelerates its degradation, has been shown to associate with the development of heart failure in mouse models and in humans. Strikingly, cMyBP-C phosphorylation presents a potential target for therapeutic development as protection against ischemic–reperfusion injury, which has been demonstrated in mouse hearts. Also, emerging evidence suggests that cMyBP-C has the potential to be used as a biomarker for diagnosing myocardial infarction. Although many aspects of cMyBP-C phosphorylation and function remain poorly understood, cMyBP-C and its phosphorylation states have significant promise as a target for therapy and for providing a better understanding of the mechanics of heart function during health and disease. In this review we discuss the most recent findings with respect to cMyBP-C phosphorylation and function and determine potential future directions to better understand the functional role of cMyBP-C and phosphorylation in sarcomeric structure, myocardial contractility and cardioprotection.

Introduction

Ischemia, myocardial infarction (MI) and heart failure (HF) constitute a growing health and economic problem. An estimated 80 million American adults have one or more types of cardiovascular disease [1]. Of these, HF afflicts approximately six million people in the U.S. each year at an estimated cost of $37 billion. HF is associated with diminished responsiveness of the β-adrenergic receptor (β-AR), loss of cardiac contractility, abnormalities in Ca²⁺ handling and altered cardiac contractile protein phosphorylation [2], [3], [4], [5]. Recent studies involving a variety of cardiovascular diseases have shown that cardiac dysfunction might result from changes in the phosphorylation states of key cardiac contractile regulatory proteins [6], [7], [8], [9]. For example, alteration in phosphorylation of contractile protein is involved in regulating myocardial dysfunction [10]. Sarcomeres are the functional unit of contraction in cardiac muscles, which consist of thick and thin filament proteins (Fig. 1). Several proteins that are post-translationally modified in the cardiac sarcomere have now been identified, including cardiac myosin binding protein-C (cMyBP-C), cardiac troponin I (cTnI), cardiac troponin T (cTnT), α-tropomyosin (α-TM) and the myosin light chain (MLC) [4], [11], [12], [13], [14]; however, in many cases the functional consequences of the post-translational modification are not known. cMyBP-C is a potential target for α- and β-adrenergic signaling in the thick filaments that are targeted by various kinases [15]. In heart muscle, phosphorylation of cMyBP-C has been shown to play an important role in sarcomeric structure and function, and protection of the heart from ischemic-reperfusion (I-R) injury [16], [17]. The objectives of this review are to discuss the role(s) of cMyBP-C phosphorylation during normal heart function and development of HF, and to identify potential areas of research that will help us understand the functional role(s) that cMyBP-C plays in vivo.