Review article
Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: Mechanisms and therapeutic opportunities

https://doi.org/10.1016/j.yjmcc.2011.01.014Get rights and content

Abstract

Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filaments of the sarcomere. Understanding the structural and functional role of cMyBP-C in the heart is clinically relevant since cMyBP-C gene mutations are a widely recognized cause of hypertrophic cardiomyopathy (HCM), which affects 0.2% of the general population. Nonsense and frameshift mutations are common in cMyBP-C and their expressions are regulated by three quality control systems, the nonsense-mediated mRNA decay, ubiquitin–proteasome system, and autophagy, which contribute to minimize the production of potential poison mutant proteins. This review discusses the structural and regulatory functions of cMyBP-C, the molecular mechanisms involved in cMyBP-C-related HCM, as well as potential causative therapies for HCM.

Research highlights

► Cardiac myosin-binding protein C (cMyBP-C) is a component of the sarcomere. ► cMyBP-C has structural and regulatory functions in cardiomyocytes. ► cMyBP-C mutations frequently cause hypertrophic cardiomyopathy (HCM). ► mRNA and protein quality control systems regulate the expression of the mutations. ► RNA-based therapies may be suitable to treat the cause of HCM.

Introduction

Contraction and relaxation of the cardiac muscle is mediated by the sliding of thick and thin filaments of the sarcomere. In addition to the principal thick and thin filaments' components, which are myosin and actin, respectively, a number of other structural and regulatory proteins are involved in sarcomere assembly, maintenance of structural integrity and regulation of contractility. Mutations in several genes encoding sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). One of the two most frequently mutated genes encodes cardiac myosin-binding protein C (cMyBP-C), which is a component of the thick filaments. Its importance in the structure and function of healthy and diseased cardiac sarcomere is underlined by the increasing amount of original works published during the last years. This review integrates our present knowledge on structural and functional roles of cMyBP-C and highlights the quality control systems regulating the expression of cMyBP-C mutations and potential causative HCM therapies.

Section snippets

Structural and regulatory functions of cMyBP-C

cMyBP-C is a member of a family comprising isoforms specific for fast-skeletal, slow-skeletal and cardiac muscles [1], encoded by distinct genes [2], [3]. The skeletal isoform was first discovered in the early 70s as a contaminant of crude myosin preparation [4] and was subsequently recognized as a novel protein of the thick filaments of the sarcomere of all vertebrate cross-striated muscles [5]. A significant body of evidence indicates that cMyBP-C has both structural and functional roles in

MYBPC3 mutations in hypertrophic cardiomyopathy

HCM is a primary disease of the myocardium characterized by left ventricular hypertrophy with a predominant involvement of the interventricular septum and is associated with myocardial and myofibrillar disarray as well as increased interstitial fibrosis [62], [63]. The overall clinical phenotype is broad, ranging from a complete absence of symptoms to diastolic dysfunction and heart failure with exertional dyspnea, chest pain and arrhythmias. HCM is considered as the most prevalent cause of

Quality control systems regulating expression of cMyBP-C mutations

There are three major quality control systems that could contribute to minimize mutant cMyBP-C production and therefore protect against myofibrillar or cellular damages induced by poison peptides. The first one is the nonsense-mediated mRNA decay (NMD), which specifically degrades nonsense transcripts. The second one is the ubiquitin–proteasome system (UPS), which is a highly selective degradation system of intracellular cytosolic, nuclear and myofibrillar proteins. The last one is autophagy,

Potential novel therapies for hypertrophic cardiomyopathy

Cardiac hypertrophy is the major determinant of mortality and morbidity, including the risk of sudden cardiac death in HCM, and also an important determinant of diastolic dysfunction and heart failure as well as susceptibility to arrhythmias. Current pharmacological treatment such as beta blockers and calcium blockers can help to reduce the stiffness in the thickened heart but are not effective in reversing cardiac hypertrophy. Therefore, the effective treatment has to target the underlying

Conclusion

A large body of evidence indicates that cMyBP-C is a key regulator of contraction and relaxation in healthy and diseased heart. Particularly, phosphorylation of cMyBP-C is important to maintain normal cardiac function and MYBPC3 mutations are one of the most frequent causes of HCM. Recent studies suggest the NMD, UPS and potentially autophagy as different quality control systems that act consecutively to efficiently eliminate or reduce the amount of mutant cMyBP-C (Fig. 5). Unravelling the

Disclosure statement

There is nothing to declare.

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (FOR-604/1-2, CA 618/1-2), the Fritz Thyssen Stiftung (Az. 10.09.1.139) and the seventh Framework Program of the European Union (Health-F2-2009-241577; Big-Heart project).

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