دورية أكاديمية
Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin
| العنوان: | Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin |
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| المؤلفون: | Toepfer, C, Wakimoto, H, Garfinkel, A, McDonough, B, Liao, D, Jiang, J, Tai, A, Gorham, J, Lunde, I, Lun, M, Lynch, T, McNamara, J, Sadayappan, S, Redwood, C, Watkins, H, Seidman, J, Seidman, C |
| بيانات النشر: | American Association for the Advancement of Science |
| سنة النشر: | 2019 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM), normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation, enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in patients with DCM, whereas inhibiting myosin by MYK-461 should benefit the substantial proportion of patients with HCM with MYBPC3 mutations. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://ora.ox.ac.uk/objects/uuid:5e4660ee-b115-4c4c-a408-0056176b3a4aTest; https://doi.org/10.1126/scitranslmed.aat1199Test |
| DOI: | 10.1126/scitranslmed.aat1199 |
| الإتاحة: | https://doi.org/10.1126/scitranslmed.aat1199Test https://ora.ox.ac.uk/objects/uuid:5e4660ee-b115-4c4c-a408-0056176b3a4aTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.C86E27CF |
| قاعدة البيانات: | BASE |
| DOI: | 10.1126/scitranslmed.aat1199 |
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