ORIGINAL RESEARCH article

Front. Physiol.

Sec. Striated Muscle Physiology

Volume 16 - 2025 | doi: 10.3389/fphys.2025.1600117

Reduction in Myofilament Ca 2+ Sensitivity Partially Ameliorates the Cardiac Phenotype in Hypertrophic Cardiomyopathy Linked to a TnT-R92Q Mutation

Provisionally accepted
Paulina LangaPaulina Langa1Angelie BaconAngelie Bacon2Chad M. WarrenChad M. Warren2Shamim A K ChowdhuryShamim A K Chowdhury2Monika HalasMonika Halas2Aurelia FernandesAurelia Fernandes2Mark David McCauleyMark David McCauley3Paul GoldspinkPaul Goldspink2R. John SolaroR. John Solaro2Beata M WolskaBeata M Wolska3*
  • 1Physiology and Biophysiscs, University of Illinois Chicago, Chicago, IL, United States
  • 2Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, United States
  • 3Medicine/Cardiology, University of Illinois Chicago, Chicago, IL, United States

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Hypertrophic cardiomyopathy (HCM) is a genetic disease caused by mutations in sarcomeric proteins. Mutations in sarcomeric proteins that give rise to cardiomyopathies produce abnormalities in the biophysical properties of the sarcomere that are propagated beyond the cardiac myocyte. In this study, we evaluated the hypothesis that early desensitization of myofilament Ca 2+ sensitivity in the TnT-R92Q mouse model, achieved through the introduction of pseudo-phosphorylated TnI (TnI-S23,24D or TnI-DD), may delay the progression of the HCM phenotype in cardiac myocyte and endothelial cellular compartments of the heart.We studied non-transgenic mice, transgenic (TG) mice expressing TnT-R92Q (TnT-R92Q), TG mice expressing TnI-DD, and double transgenic mice expressing TnT-R92Q and TnI-DD at 28 days and 16 weeks of age. Experiments reported here demonstrate that expression of TnI-DD in the TnT-R92Q HCM mouse model results in partial normalization of myofilament Ca 2+ sensitivity, improved cardiac morphology and function, reduced fibrosis, normalization of YAP signaling in endothelial cells, but a lack of normalization of coronary flow parameters.The novelty of the approach reported here highlights that although small corrections made to offset the sarcomeric defect may not fully or immediately resolve the disease's pathophysiologic state, they can lessen the severity of HCM. Our findings further support the concept that early desensitization of myofilaments to Ca 2+ in HCM, mainly when arising from mutations in thin filament proteins, represents a promising avenue for developing new therapeutic drugs.

Keywords: Hypertrophic Cardiomyopathy, Myofilament Ca 2+ sensitivity, Fibrosis, YAP signaling, Coronary flow, Thin filaments

Received: 25 Mar 2025; Accepted: 07 May 2025.

Copyright: © 2025 Langa, Bacon, Warren, Chowdhury, Halas, Fernandes, McCauley, Goldspink, Solaro and Wolska. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Beata M Wolska, Medicine/Cardiology, University of Illinois Chicago, Chicago, 60612, IL, United States

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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