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Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition.

ABSTRACT: Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. Here, we present an optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm, allowing the systematic study of a large set of HCM mutations and the definition of different mutation classes based on their effects on lever arm compliance, sequestered state stability, and motor functions. The present work reconciles previous models and explains how distinct HCM mutations can have disparate effects on the motor mechano-chemical parameters and yet lead to the same disease. The framework presented here can guide future investigations aiming at finding HCM treatments.

SUBMITTER: Robert-Paganin J

PROVIDER: S-EPMC6167380 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition.

Robert-Paganin Julien J Auguin Daniel D Houdusse Anne A

Nature communications 20181001 1

Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. Here, we present an optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the ...[more]

PMID: 30275503

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Project description:AIMS:A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-C?C10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-C?C10mutin vivo are unknown. We hypothesized that expression of cMyBP-C?C10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. METHODS AND RESULTS:To determine whether expression of cMyBP-C?C10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-C?C10mut at approximately half the level of endogenous cMyBP-C. At 12?weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-C?C10mut (heart weight/body weight ratio: 4.43?±?0.11?mg/g non-transgenic (NTG) vs. 5.34?±?0.25?mg/g cMyBP-C?C10mut, P?<?0.05). Furthermore, haematoxylin and eosin, Masson's trichrome staining, as well as second-harmonic generation imaging revealed the presence of significant fibrosis and a greater relative nuclear area in cMyBP-C?C10mut hearts compared with NTG controls. M-mode echocardiography analysis revealed hypercontractile hearts (EF: 53.4%±2.9% NTG vs. 66.4% ± 4.7% cMyBP-C?C10mut; P?<?0.05) and early diastolic dysfunction (E/E': 28.7?±?3.7 NTG vs. 46.3?±?8.4 cMyBP-C?C10mut; P?<?0.05), indicating the presence of an HCM phenotype. To assess whether these changes manifested at the myofilament level, contractile function of single skinned cardiomyocytes was measured. Preserved maximum force generation and increased Ca2+-sensitivity of force generation were observed in cardiomyocytes from cMyBP-C?C10mut mice compared with NTG controls (EC50: 3.6?±?0.02?µM NTG vs. 2.90?±?0.01?µM cMyBP-C?C10mut; P?<?0.0001). CONCLUSION:Expression of cMyBP-C protein with a modified C10 domain is sufficient to cause contractile dysfunction and HCM in vivo.

Dataset Information

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition.

Publications

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition.

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