Carrington, Glenn;
Hau, Hoi Ting Abbi;
Kosta, Sarah;
Dugdale, Hannah F;
Muntoni, Francesco;
D'Amico, Adele;
Van den Bergh, Peter YK;
... Ochala, Julien; + view all
(2023)
Human Skeletal myopathy myosin mutations disrupt myosin head sequestration.
JCI Insight
, 8
(21)
, Article e172322. 10.1172/jci.insight.172322.
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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 analyse the effects of common MYH7 and MYH2 mutations in the light meromyosin region of myosin (LMM). Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in-silico modelling showed that myosin coiled-coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients, and Mant-ATP 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, myofibre mechanics experiments to investigate contractile function showed myofibre contractility was not affected. These findings indicate that the structural remodelling 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.
| Type: | Article |
|---|---|
| Title: | Human Skeletal myopathy myosin mutations disrupt myosin head sequestration |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/jci.insight.172322 |
| Publisher version: | https://doi.org/10.1172/jci.insight.172322 |
| Language: | English |
| Additional information: | Copyright: © 2023 Carrington et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Keywords: | Genetic diseases, Muscle Biology, Neuromuscular disease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10178305 |
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