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Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin

In this study, we investigated the role of the super-relaxed (SRX) state of myosin in the structure–function relationship of sarcomeres in the hearts of mouse models of cardiomyopathy-bearing mutations in the human ventricular regulatory light chain (RLC, MYL2 gene). Skinned papillary muscles from h...

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Detalles Bibliográficos
Autores principales: Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Ma, Weikang, Irving, Thomas C., Szczesna-Cordary, Danuta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8872785/
https://www.ncbi.nlm.nih.gov/pubmed/35177471
http://dx.doi.org/10.1073/pnas.2110328119
Descripción
Sumario:In this study, we investigated the role of the super-relaxed (SRX) state of myosin in the structure–function relationship of sarcomeres in the hearts of mouse models of cardiomyopathy-bearing mutations in the human ventricular regulatory light chain (RLC, MYL2 gene). Skinned papillary muscles from hypertrophic (HCM–D166V) and dilated (DCM–D94A) cardiomyopathy models were subjected to small-angle X-ray diffraction simultaneously with isometric force measurements to obtain the interfilament lattice spacing and equatorial intensity ratios (I(11)/I(10)) together with the force-pCa relationship over a full range of [Ca(2+)] and at a sarcomere length of 2.1 μm. In parallel, we studied the effect of mutations on the ATP-dependent myosin energetic states. Compared with wild-type (WT) and DCM–D94A mice, HCM–D166V significantly increased the Ca(2+) sensitivity of force and left shifted the I(11)/I(10)-pCa relationship, indicating an apparent movement of HCM–D166V cross-bridges closer to actin-containing thin filaments, thereby allowing for their premature Ca(2+) activation. The HCM–D166V model also disrupted the SRX state and promoted an SRX-to-DRX (super-relaxed to disordered relaxed) transition that correlated with an HCM-linked phenotype of hypercontractility. While this dysregulation of SRX ↔ DRX equilibrium was consistent with repositioning of myosin motors closer to the thin filaments and with increased force-pCa dependence for HCM–D166V, the DCM–D94A model favored the energy-conserving SRX state, but the structure/function–pCa data were similar to WT. Our results suggest that the mutation-induced redistribution of myosin energetic states is one of the key mechanisms contributing to the development of complex clinical phenotypes associated with human HCM–D166V and DCM–D94A mutations.