Human skeletal myopathy myosin mutations disrupt myosin head sequestration
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 appro...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.172322 |
| _version_ | 1797634217971023872 |
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| author | Glenn Carrington Abbi Hau Sarah Kosta Hannah F. Dugdale Francesco Muntoni Adele D’Amico Peter Van den Bergh Norma B. Romero Edoardo Malfatti Juan Jesus Vilchez Anders Oldfors Sander Pajusalu Katrin Õunap Marta Giralt-Pujol Edmar Zanoteli Kenneth S. Campbell Hiroyuki Iwamoto Michelle Peckham Julien Ochala |
| author_facet | Glenn Carrington Abbi Hau Sarah Kosta Hannah F. Dugdale Francesco Muntoni Adele D’Amico Peter Van den Bergh Norma B. Romero Edoardo Malfatti Juan Jesus Vilchez Anders Oldfors Sander Pajusalu Katrin Õunap Marta Giralt-Pujol Edmar Zanoteli Kenneth S. Campbell Hiroyuki Iwamoto Michelle Peckham Julien Ochala |
| author_sort | Glenn Carrington |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:05:34Z |
| format | Article |
| id | doaj.art-59ff4fd339fd4cbaa9a588a2470f9192 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:34Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-59ff4fd339fd4cbaa9a588a2470f91922023-11-07T16:26:22ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01821Human skeletal myopathy myosin mutations disrupt myosin head sequestrationGlenn CarringtonAbbi HauSarah KostaHannah F. DugdaleFrancesco MuntoniAdele D’AmicoPeter Van den BerghNorma B. RomeroEdoardo MalfattiJuan Jesus VilchezAnders OldforsSander PajusaluKatrin ÕunapMarta Giralt-PujolEdmar ZanoteliKenneth S. CampbellHiroyuki IwamotoMichelle PeckhamJulien OchalaMyosin 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.https://doi.org/10.1172/jci.insight.172322Muscle biology |
| spellingShingle | Glenn Carrington Abbi Hau Sarah Kosta Hannah F. Dugdale Francesco Muntoni Adele D’Amico Peter Van den Bergh Norma B. Romero Edoardo Malfatti Juan Jesus Vilchez Anders Oldfors Sander Pajusalu Katrin Õunap Marta Giralt-Pujol Edmar Zanoteli Kenneth S. Campbell Hiroyuki Iwamoto Michelle Peckham Julien Ochala Human skeletal myopathy myosin mutations disrupt myosin head sequestration JCI Insight Muscle biology |
| title | Human skeletal myopathy myosin mutations disrupt myosin head sequestration |
| title_full | Human skeletal myopathy myosin mutations disrupt myosin head sequestration |
| title_fullStr | Human skeletal myopathy myosin mutations disrupt myosin head sequestration |
| title_full_unstemmed | Human skeletal myopathy myosin mutations disrupt myosin head sequestration |
| title_short | Human skeletal myopathy myosin mutations disrupt myosin head sequestration |
| title_sort | human skeletal myopathy myosin mutations disrupt myosin head sequestration |
| topic | Muscle biology |
| url | https://doi.org/10.1172/jci.insight.172322 |
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