Carrington, G., Hau, A., Kosta, S. et al. (16 more authors) (2023) Human skeletal myopathy myosin mutations disrupt myosin head sequestration. JCI Insight, 8 (21). e172322. ISSN 2379-3708
Abstract
Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023, Carrington et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
Keywords: | Muscle, Skeletal; Humans; Muscular Diseases; Myosins; Adenosine Triphosphate; Mutation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cell Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Jun 2024 16:00 |
Last Modified: | 19 Jun 2024 16:00 |
Status: | Published |
Publisher: | American Society for Clinical Investigation |
Identification Number: | 10.1172/jci.insight.172322 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:213624 |
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