The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy

Wolska, Beata M.; Langa, Paulina; Solaro, R. John

doi:10.53941/ijddp.v1i1.189

Cited by 5 publications

(2 citation statements)

References 43 publications

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“…Advances in transcriptomic and proteomic approaches provide a snapshot of a particular state but information on stages of the progression DCM with and without therapeutic interventions to test for pleiotropic effects would be ideal. Although not described here owing to limitations there is a need for consideration of reciprocal interactions of the myocytes with the mosaic of changes within micro-environment [116,117]. Fibrosis, for example, has been well documented confirming non-invasive measurements and validating a link with DCM severity.…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 81%

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Preprint

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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.

show abstract

Section: Future Directions and Concluding Remarksmentioning

confidence: 81%

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Advances in transcriptomic and proteomic approaches provide a snapshot of a particular state but information on stages of the DCM progression with and without therapeutic interventions to test for pleiotropic effects would be ideal. Although not described here owing to limitations, there is a need for the consideration of reciprocal interactions of the myocytes with the mosaic of changes within the micro-environment [121,122]. The diagnosis of severity of DCM has been made with non-invasive measurement of fibrosis, which has been validated with well-documented determinations of the presence of fibrosis [118].…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Biomedicines

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Novel therapies for the treatment of familial dilated cardiomyopathy (DCM) are lacking. Shaping research directions to clinical needs is critical. 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 concerning mutant proteins and their impact on sarcomere molecular signaling are currently controversial. 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 the Ca2+ 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 the control of tension. We discuss these mechanisms that lead to different ideas related to how tension is disturbed by levels of mutant sarcomere proteins linked to the expression of gene variants in the complex landscape of DCM. 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.

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The Role of Cardiac Troponin and Other Emerging Biomarkers Among Athletes and Beyond: Underlying Mechanisms, Differential Diagnosis, and Guide for Interpretation

Celeski,

Segreti,

Crisci

et al. 2024

Biomolecules

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Cardiovascular (CV) disease remains the leading cause of morbidity and mortality worldwide, highlighting the necessity of understanding its underlying molecular and pathophysiological pathways. Conversely, physical activity (PA) and exercise are key strategies in reducing CV event risks. Detecting latent CV conditions in apparently healthy individuals, such as athletes, presents a unique challenge. The early identification and treatment of CV disorders are vital for long-term health and patient survival. Cardiac troponin is currently the most commonly used biomarker for assessing CV changes in both athletes and the general population. However, there remains considerable debate surrounding the mechanisms underlying exercise-induced troponin elevations and its release in non-ischemic contexts. Thus, there is a pressing need to identify and implement more sensitive and specific biomarkers for CV disorders in clinical practice. Indeed, research continues to explore reliable biomarkers for evaluating the health of athletes and the effectiveness of physical exercise. It is essential to analyze current evidence on troponin release in non-ischemic conditions, post-strenuous exercise, and the complex biological pathways that influence its detection. Furthermore, this study summarizes current research on cytokines and exosomes, including their physiological roles and their relevance in various CV conditions, especially in athletes. In addition, this paper gives special attention to underlying mechanisms, potential biomarkers, and future perspectives.

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The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy

Cited by 5 publications

References 43 publications

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

The Role of Cardiac Troponin and Other Emerging Biomarkers Among Athletes and Beyond: Underlying Mechanisms, Differential Diagnosis, and Guide for Interpretation

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