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

Chen Ching Yuan, Katarzyna Kazmierczak, Jingsheng Liang, Weikang Ma, Thomas C. Irving, Danuta Szczesna-Cordary

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 (I11/I10) together with the force-pCa relationship over a full range of [Ca2+] 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 Ca2+ sensitivity of force and left shifted the I11/I10-pCa relationship, indicating an apparent movement of HCM–D166V cross-bridges closer to actin-containing thin filaments, thereby allowing for their premature Ca2+ 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.

Original languageEnglish (US)
Article numbere2110328119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number8
DOIs
StatePublished - Feb 22 2022
Externally publishedYes

Keywords

  • Equatorial intensity ratio
  • Interfilament lattice spacing
  • Isometric force
  • Super-relaxed state of myosin
  • Transgenic RLC mice

ASJC Scopus subject areas

  • General

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