Solaro, R.J.; Goldspink, P.H.; Wolska, B.M. Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies. Preprints2024, 2024031545. https://doi.org/10.20944/preprints202403.1545.v1
APA Style
Solaro, R.J., Goldspink, P.H., & Wolska, B.M. (2024). Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies. Preprints. https://doi.org/10.20944/preprints202403.1545.v1
Chicago/Turabian Style
Solaro, R.J., Paul H. Goldspink and Beata M. Wolska. 2024 "Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies" Preprints. https://doi.org/10.20944/preprints202403.1545.v1
Abstract
Novel therapies for treatment of familial dilated cardiomyopathy (DCM) are lacking. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment which over time result in structural and functional maladaptations leading to heart failure (HF). Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly in relation to mutant proteins and their impact on sarcomere molecular signaling, are currently the subject of controversy. Thus, there is a need for clarification as to how mutant proteins affect sarcomere molecular signaling in the etiology and progression of DCM. A main topic in this controversy is the control of the number of tension generating myosin heads reacting with the thin filament. One line of investigation proposes that this number is determined by changes in the ratio of myosin heads in a sequestered super-relaxed state (SRX) or in a disordered relaxed state (DRX) poised for force generation upon Ca-activation of the thin filament. Contrasting evidence from nanometer–micrometer-scale x-ray diffraction in intact trabeculae indicates that the SRX/DRX states may have a lesser role. Instead, the proposal is that myosin heads are in a basal OFF state in relaxation then transfer to an ON state through a mechano-sensing mechanism induced during early thin filament activation and increasing thick filament strain. Recent evidence about the modulation of these mechanisms by protein phosphorylation has also introduced a need for reconsidering control of tension. We discuss these mechanisms that lead to different ideas related to how tension is controlled and disturbed by mutant sarcomere proteins linked to DCM including cardiac myosin, myosin-binding protein C, titin filaments, and thin filaments. Resolving the various mechanisms and incorporating them into a unified concept is crucial for gaining a comprehensive understanding of DCM. This deeper understanding is not only important for diagnosis and treatment strategies with small molecules, but also for understanding the reciprocal signaling processes that occur between cardiac myocytes and their micro-environment. By unraveling these complexities, we can pave the way for improved therapeutic interventions for managing DCM.
Keywords
Sarcomere Disease Genes; TTI; Myosin Control Mechanisms; Sarcomere Activators; Precision Medicine
Subject
Medicine and Pharmacology, Cardiac and Cardiovascular Systems
Copyright:
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