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Molecular Pharmacology

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Research ArticleArticle

Effects of Sarcomere Activators and Inhibitors Targeting Myosin Cross-Bridges on Ca2+-Activation of Mature and Immature Mouse Cardiac Myofilaments

Monika Halas, Paulina Langa, Chad M. Warren, Paul H. Goldspink, Beata M. Wolska and R. John Solaro
Molecular Pharmacology May 2022, 101 (5) 286-299; DOI: https://doi.org/10.1124/molpharm.121.000420
Monika Halas
Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine (M.H., P.L., C.M.W., P.H.G., B.M.W., R.J.S.) and Department of Medicine, Division of Cardiology (B.M.W.), University of Illinois at Chicago, Chicago, Illinois
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Paulina Langa
Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine (M.H., P.L., C.M.W., P.H.G., B.M.W., R.J.S.) and Department of Medicine, Division of Cardiology (B.M.W.), University of Illinois at Chicago, Chicago, Illinois
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Chad M. Warren
Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine (M.H., P.L., C.M.W., P.H.G., B.M.W., R.J.S.) and Department of Medicine, Division of Cardiology (B.M.W.), University of Illinois at Chicago, Chicago, Illinois
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Paul H. Goldspink
Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine (M.H., P.L., C.M.W., P.H.G., B.M.W., R.J.S.) and Department of Medicine, Division of Cardiology (B.M.W.), University of Illinois at Chicago, Chicago, Illinois
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Beata M. Wolska
Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine (M.H., P.L., C.M.W., P.H.G., B.M.W., R.J.S.) and Department of Medicine, Division of Cardiology (B.M.W.), University of Illinois at Chicago, Chicago, Illinois
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R. John Solaro
Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine (M.H., P.L., C.M.W., P.H.G., B.M.W., R.J.S.) and Department of Medicine, Division of Cardiology (B.M.W.), University of Illinois at Chicago, Chicago, Illinois
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Abstract

We tested the hypothesis that isoform shifts in sarcomeres of the immature heart modify the effect of cardiac myosin-directed sarcomere inhibitors and activators. Omecamtiv mecarbil (OM) activates tension and is in clinical trials for the treatment of adult acute and chronic heart failure. Mavacamten (Mava) inhibits tension and is in clinical trials to relieve hypercontractility and outflow obstruction in advanced genetic hypertrophic cardiomyopathy (HCM), which is often linked to mutations in sarcomeric proteins. To address the effect of these agents in developing sarcomeres, we isolated heart fiber bundles, extracted membranes with Triton X-100, and measured tension developed over a range of Ca2+ concentrations with and without OM or Mava treatment. We made measurements in fiber bundles from hearts of adult nontransgenic (NTG) controls expressing cardiac troponin I (cTnI), and from hearts of transgenic (TG-ssTnI) mice expressing the fetal/neonatal form, slow skeletal troponin I (ssTnI). We also compared fibers from 7- and 14-day-old NTG mice expressing ssTnI and cTnI. These studies were repeated with 7- and 14-day-old transgenic mice (TG-cTnT-R92Q) expressing a mutant form of cardiac troponin T (cTnT) linked to HCM. OM increased Ca2+-sensitivity and decreased cooperative activation in both ssTnI- and cTnI-regulated myofilaments with a similar effect: reducing submaximal tension in immature and mature myofilaments. Although Mava decreased tension similarly in cTnI- and ssTnI-regulated myofilaments controlled either by cTnT or cTnT-R92Q, its effect involved a depressed Ca2+-sensitivity in the mature cTnT-R92 myofilaments. Our data demonstrate an influence of myosin and thin-filament associated proteins on the actions of myosin-directed agents such as OM and Mava.

SIGNIFICANCE STATEMENT The effects of myosin-targeted activators and inhibitors on Ca2+-activated tension in developing cardiac sarcomeres presented here provide novel, ex vivo evidence as to their actions in early-stage cardiac disorders. These studies advance understanding of the molecular mechanisms of these agents, which are important in preclinical studies employing sarcomere Ca2+-response as a screening approach. The data also inform the use of commonly immature cardiac myocytes generated from human-inducible pluripotent stem cells in screening for sarcomere activators and inhibitors.

Footnotes

    • Received September 28, 2021.
    • Accepted February 16, 2022.
  • ↵1 M.H. and P.L. contributed equally to this work.

  • This work was supported by National Institutes of Health National Heart Lung and Blood Institute [Grant R01-HL128468] to J.S. and B.M.W. and [Grant P01-HL062426] to R.J.S., C.M.W., B.M.W., and P.H.G.; and the American Heart Association [Grant 834691] to P.L.

  • Dr. Solaro is a member of the Scientific Advisory Board of Cytokinetics and a consultant to MyoKardia BMS and Pfizer, Inc.

  • https://doi.org/10.1124/molpharm.121.000420.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 101 (5)
Molecular Pharmacology
Vol. 101, Issue 5
1 May 2022
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Research ArticleArticle

Myosin Activators/Inhibitors in Immature Cardiac Sarcomeres

Monika Halas, Paulina Langa, Chad M. Warren, Paul H. Goldspink, Beata M. Wolska and R. John Solaro
Molecular Pharmacology May 1, 2022, 101 (5) 286-299; DOI: https://doi.org/10.1124/molpharm.121.000420

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Research ArticleArticle

Myosin Activators/Inhibitors in Immature Cardiac Sarcomeres

Monika Halas, Paulina Langa, Chad M. Warren, Paul H. Goldspink, Beata M. Wolska and R. John Solaro
Molecular Pharmacology May 1, 2022, 101 (5) 286-299; DOI: https://doi.org/10.1124/molpharm.121.000420
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