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 »
- Authors:
-
- Univ. of Miami Miller School of Medicine, FL (United States)
- Illinois Institute of Technology, Chicago, IL (United States)
- Publication Date:
- 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
Citation Formats
Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Ma, Weikang, Irving, Thomas C., and Szczesna-Cordary, Danuta. Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin. United States: N. p., 2022.
Web. doi:10.1073/pnas.2110328119.
Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Ma, Weikang, Irving, Thomas C., & Szczesna-Cordary, Danuta. Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin. United States. https://doi.org/10.1073/pnas.2110328119
Yuan, Chen-Ching, Kazmierczak, Katarzyna, Liang, Jingsheng, Ma, Weikang, Irving, Thomas C., and Szczesna-Cordary, Danuta. Thu .
"Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin". United States. https://doi.org/10.1073/pnas.2110328119. https://www.osti.gov/servlets/purl/1856362.
@article{osti_1856362,
title = {Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin},
author = {Yuan, Chen-Ching and Kazmierczak, Katarzyna and Liang, Jingsheng and Ma, Weikang and Irving, Thomas C. and Szczesna-Cordary, Danuta},
abstractNote = {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–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.},
doi = {10.1073/pnas.2110328119},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 8,
volume = 119,
place = {United States},
year = {Thu Feb 17 00:00:00 EST 2022},
month = {Thu Feb 17 00:00:00 EST 2022}
}
Works referenced in this record:
Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains
journal, January 2019
- Yadav, Sunil; Sitbon, Yoel H.; Kazmierczak, Katarzyna
- Pflügers Archiv - European Journal of Physiology, Vol. 471, Issue 5
Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations
journal, February 2019
- Spudich, James A.
- Pflügers Archiv - European Journal of Physiology, Vol. 471, Issue 5
Phosphomimetic‐mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain
journal, November 2018
- Yadav, Sunil; Kazmierczak, Katarzyna; Liang, Jingsheng
- The FEBS Journal, Vol. 286, Issue 1
Phosphorylation of myosin regulatory light chain controls myosin head conformation in cardiac muscle
journal, August 2015
- Kampourakis, Thomas; Irving, Malcolm
- Journal of Molecular and Cellular Cardiology, Vol. 85
Normality Tests for Statistical Analysis: A Guide for Non-Statisticians
journal, December 2012
- Ghasemi, Asghar; Zahediasl, Saleh
- International Journal of Endocrinology and Metabolism, Vol. 10, Issue 2
Filament lattice of frog striated muscle. Radial forces, lattice stability, and filament compression in the A-band of relaxed and rigor muscle
journal, September 1988
- Millman, B. M.; Irving, T. C.
- Biophysical Journal, Vol. 54, Issue 3
The role of super-relaxed myosin in skeletal and cardiac muscle
journal, December 2014
- McNamara, James W.; Li, Amy; dos Remedios, Cristobal G.
- Biophysical Reviews, Vol. 7, Issue 1
New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy
journal, March 2015
- Semsarian, Christopher; Ingles, Jodie; Maron, Martin S.
- Journal of the American College of Cardiology, Vol. 65, Issue 12
Hypertrophic Cardiomyopathy: Distribution of Disease Genes, Spectrum of Mutations, and Implications for a Molecular Diagnosis Strategy
journal, May 2003
- Richard, Pascale; Charron, Philippe; Carrier, Lucie
- Circulation, Vol. 107, Issue 17
Basal myosin light chain phosphorylation is a determinant of Ca 2+ sensitivity of force and activation dependence of the kinetics of myocardial force development
journal, December 2004
- Olsson, M. Charlotte; Patel, Jitandrakumar R.; Fitzsimons, Daniel P.
- American Journal of Physiology-Heart and Circulatory Physiology, Vol. 287, Issue 6
Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle
journal, October 2018
- Gonzalez-Martinez, David; Johnston, Jamie R.; Landim-Vieira, Maicon
- Journal of Molecular and Cellular Cardiology, Vol. 123
Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy
journal, March 2020
- Toepfer, Christopher N.; Garfinkel, Amanda C.; Venturini, Gabriela
- Circulation, Vol. 141, Issue 10
Stretching the lever-arm theory
journal, January 2002
- Geeves, Michael A.
- Nature, Vol. 415, Issue 6868
Familial Hypertrophic Cardiomyopathy Mutations in the Regulatory Light Chains of Myosin Affect Their Structure, Ca 2+ Binding, and Phosphorylation
journal, December 2000
- Szczesna, Danuta; Ghosh, Debalina; Li, Qi
- Journal of Biological Chemistry, Vol. 276, Issue 10
Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development: X-ray studies of RLC phosphorylation in skinned murine cardiac muscle
journal, March 2010
- Colson, Brett A.; Locher, Matthew R.; Bekyarova, Tanya
- The Journal of Physiology, Vol. 588, Issue 6
Three-dimensional structure of myosin subfragment-1: a molecular motor
journal, July 1993
- Rayment, I.; Rypniewski, W.; Schmidt-Base, K.
- Science, Vol. 261, Issue 5117
Prolonged Ca2+ and Force Transients in Myosin RLC Transgenic Mouse Fibers Expressing Malignant and Benign FHC Mutations
journal, August 2006
- Wang, Ying; Xu, Yuanyuan; Kerrick, W. Glenn L.
- Journal of Molecular Biology, Vol. 361, Issue 2
Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy
journal, January 2017
- Yadav, Sunil; Szczesna-Cordary, Danuta
- Biophysical Reviews, Vol. 9, Issue 1
Cardiac myosin super relaxation (SRX): a perspective on fundamental biology, human disease and therapeutics
journal, February 2021
- Schmid, Manuel; Toepfer, Christopher N.
- Biology Open, Vol. 10, Issue 2
Three-dimensional structure of vertebrate cardiac muscle myosin filaments
journal, February 2008
- Zoghbi, M. E.; Woodhead, J. L.; Moss, R. L.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 7
Myosin dynamics during relaxation in mouse soleus muscle and modulation by 2′‐deoxy‐ATP
journal, September 2020
- Ma, Weikang; Childers, Matthew; Murray, Jason
- The Journal of Physiology, Vol. 598, Issue 22
Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes
journal, June 2017
- Alamo, Lorenzo; Ware, James S.; Pinto, Antonio
- eLife, Vol. 6
Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice
journal, June 2015
- Yuan, Chen-Ching; Muthu, Priya; Kazmierczak, Katarzyna
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 30
In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain
journal, June 2014
- Muthu, Priya; Liang, Jingsheng; Schmidt, William
- Archives of Biochemistry and Biophysics, Vol. 552-553
Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca 2+ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction
journal, November 2003
- Szczesna-Cordary, Danuta; Guzman, Georgianna; Ng, Shuk-Shin
- Journal of Biological Chemistry, Vol. 279, Issue 5
Hypertrophic and Dilated Cardiomyopathy: Four Decades of Basic Research on Muscle Lead to Potential Therapeutic Approaches to These Devastating Genetic Diseases
journal, March 2014
- Spudich, James A.
- Biophysical Journal, Vol. 106, Issue 6
SuperPlots: Communicating reproducibility and variability in cell biology
journal, April 2020
- Lord, Samuel J.; Velle, Katrina B.; Mullins, R. Dyche
- Journal of Cell Biology, Vol. 219, Issue 6
Insights into myosin regulatory and essential light chains: a focus on their roles in cardiac and skeletal muscle function, development and disease
journal, May 2019
- Sitbon, Yoel H.; Yadav, Sunil; Kazmierczak, Katarzyna
- Journal of Muscle Research and Cell Motility
Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain
journal, April 2015
- Huang, Wenrui; Liang, Jingsheng; Yuan, Chen-Ching
- FEBS Journal, Vol. 282, Issue 12
Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light
journal, July 2017
- Trivedi, Darshan V.; Adhikari, Arjun S.; Sarkar, Saswata S.
- Biophysical Reviews, Vol. 10, Issue 1
Ablation of the N terminus of cardiac essential light chain promotes the super‐relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice
journal, February 2020
- Sitbon, Yoel H.; Kazmierczak, Katarzyna; Liang, Jingsheng
- The FEBS Journal, Vol. 287, Issue 18
Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers
journal, August 2018
- Anderson, Robert L.; Trivedi, Darshan V.; Sarkar, Saswata S.
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 35
Regulatory Light Chains of Striated Muscle Myosin. Structure, Function and Malfunction
journal, June 2003
- Szczesna-Cordary, Danuta
- Current Drug Target -Cardiovascular & Hematological Disorders, Vol. 3, Issue 2
Direct detection of the myosin super-relaxed state and interacting-heads motif in solution
journal, October 2021
- Chu, Sami; Muretta, Joseph M.; Thomas, David D.
- Journal of Biological Chemistry, Vol. 297, Issue 4
Genetic Pathogenesis of Hypertrophic and Dilated Cardiomyopathy
journal, April 2018
- Garfinkel, Amanda C.; Seidman, Jonathan G.; Seidman, Christine E.
- Heart Failure Clinics, Vol. 14, Issue 2
Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers
journal, December 2009
- Stewart, M. A.; Franks-Skiba, K.; Chen, S.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 1
Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice
journal, March 2009
- Kerrick, W. Glenn L.; Kazmierczak, Katarzyna; Xu, Yuanyuan
- The FASEB Journal, Vol. 23, Issue 3
Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility
journal, May 2010
- Huke, Sabine; Knollmann, Björn C.
- Journal of Molecular and Cellular Cardiology, Vol. 48, Issue 5
Constitutive Phosphorylation of Cardiac Myosin Regulatory Light Chain in Vivo
journal, March 2015
- Chang, Audrey N.; Battiprolu, Pavan K.; Cowley, Patrick M.
- Journal of Biological Chemistry, Vol. 290, Issue 17
Changes in thick filament structure during compression of the filament lattice in relaxed frog sartorius muscle
journal, October 1989
- Irving, Thomas C.; Millman, Barry M.
- Journal of Muscle Research and Cell Motility, Vol. 10, Issue 5
A New State of Cardiac Myosin with Very Slow ATP Turnover: A Potential Cardioprotective Mechanism in the Heart
journal, April 2011
- Hooijman, Pleuni; Stewart, Melanie A.; Cooke, Roger
- Biophysical Journal, Vol. 100, Issue 8
Conserved Intramolecular Interactions Maintain Myosin Interacting-Heads Motifs Explaining Tarantula Muscle Super-Relaxed State Structural Basis
journal, March 2016
- Alamo, Lorenzo; Qi, Dan; Wriggers, Willy
- Journal of Molecular Biology, Vol. 428, Issue 6
Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice
journal, February 2018
- Yuan, Chen-Ching; Kazmierczak, Katarzyna; Liang, Jingsheng
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 10