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

Abstract

Here, 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–D94Amore » 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.« less

Authors:

Yuan, Chen-Ching ^[1]; Kazmierczak, Katarzyna ^[1]; Liang, Jingsheng ^[1]; Ma, Weikang ^[2]; Irving, Thomas C.  ^[2];

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Szczesna-Cordary, Danuta  ^[1]

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• Search DOE PAGES for ORCID "0000-0002-8441-0722"

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+ Show Author Affiliations

1. Univ. of Miami Miller School of Medicine, FL (United States)
2. Illinois Institute of Technology, Chicago, IL (United States)

Publication Date:

Thu Feb 17 00:00:00 EST 2022

Research Org.:

Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:

USDOE Office of Science (SC); National Institutes of Health (NIH)

OSTI Identifier:

1856362

Alternate Identifier(s):

OSTI ID: 1901330

Grant/Contract Number:  

AC02-06CH11357; R01-HL143830; R56-HL146133; P41-GM103622

Resource Type:

Accepted Manuscript

Journal Name:

Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:

Journal Volume: 119; Journal Issue: 8; Journal ID: ISSN 0027-8424

Publisher:

National Academy of Sciences

Country of Publication:

United States

Language:

ENGLISH

Subject:

59 BASIC BIOLOGICAL SCIENCES; super-relaxed state of myosin; interfilament lattice spacing; equatorial intensity ratio; isometric force; transgenic RLC mice