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Review
. 2022 Mar;596(6):703-746.
doi: 10.1002/1873-3468.14301. Epub 2022 Feb 28.

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP-C

Carmen Suay-Corredera  1 , Jorge Alegre-Cebollada  1
Affiliations
Free article
Review

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP-C

Carmen Suay-Corredera et al. FEBS Lett. 2022 Mar.
Free article

Abstract

Hypertrophic cardiomyopathy (HCM), a disease characterized by cardiac muscle hypertrophy and hypercontractility, is the most frequently inherited disorder of the heart. HCM is mainly caused by variants in genes encoding proteins of the sarcomere, the basic contractile unit of cardiomyocytes. The most frequently mutated among them is MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), a key regulator of sarcomere contraction. In this review, we summarize clinical and genetic aspects of HCM and provide updated information on the function of the healthy and HCM sarcomere, as well as on emerging therapeutic options targeting sarcomere mechanical activity. Building on what is known about cMyBP-C activity, we examine different pathogenicity drivers by which MYBPC3 variants can cause disease, focussing on protein haploinsufficiency as a common pathomechanism also in nontruncating variants. Finally, we discuss recent evidence correlating altered cMyBP-C mechanical properties with HCM development.

Keywords: RNA splicing; cardiac myosin-binding protein C; hypertrophic cardiomyopathy; myosin; nontruncating MYBPC3 variants; protein nanomechanics; protein stability; sarcomere contraction; truncating MYBPC3 variants; variants of uncertain significance.

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