Ensemble Force Changes that Result from Human Cardiac Myosin Mutations and a Small-Molecule Effector
Cardiomyopathies due to mutations in human β-cardiac myosin are a significant cause of heart failure, sudden death, and arrhythmia. To understand the underlying molecular basis of changes in the contractile system’s force production due to such mutations and search for potential drugs that restore f...
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Published in | Cell reports (Cambridge) Vol. 11; no. 6; pp. 910 - 920 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
12.05.2015
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | Cardiomyopathies due to mutations in human β-cardiac myosin are a significant cause of heart failure, sudden death, and arrhythmia. To understand the underlying molecular basis of changes in the contractile system’s force production due to such mutations and search for potential drugs that restore force generation, an in vitro assay is necessary to evaluate cardiac myosin’s ensemble force using purified proteins. Here, we characterize the ensemble force of human α- and β-cardiac myosin isoforms and those of β-cardiac myosins carrying left ventricular non-compaction (M531R) and dilated cardiomyopathy (S532P) mutations using a utrophin-based loaded in vitro motility assay and new filament-tracking software. Our results show that human α- and β-cardiac myosin, as well as the mutants, show opposite mechanical and enzymatic phenotypes with respect to each other. We also show that omecamtiv mecarbil, a previously discovered cardiac-specific myosin activator, increases β-cardiac myosin force generation.
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•In vitro assay and analysis software measures human cardiac myosin power output•α-Cardiac myosin has higher velocity but generates less force than β-cardiac myosin•M531R and S532P respectively increase and decrease β-cardiac myosin force output•Omecamtiv mecarbil increases β-cardiac myosin force but decreases its velocity
Aksel et al. use a customized assay and rapid-analysis software to show that ventricle-specific β-cardiac myosin generates higher ensemble force than the atrium-specific α isoform—two mutations associated with different clinical phenotypes alter cardiac myosin ensemble force differently—and omecamtiv mecarbil increases cardiac myosin ensemble force. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2015.04.006 |