Unraveling the Molecular Mechanisms of Heart and Skeletal Muscle Pathologies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 1094

Special Issue Editors


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Guest Editor
Institute of Genetic and Biomedical Research—National Research Council (IRGB-CNR), Milan Unit at Humanitas Research Hospital, Milan, Italy
Interests: cardiac muscle; skeletal muscle; sarcomere; cardiomyopathies; skeletal myopathies; animal models

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Guest Editor
Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Université Paris Est, U955 INSERM, EnvA, EFS, IMRB, F-94010 and APHP, Henri Mondor Hospital, 94010 Créteil, France
Interests: neuromuscular disorders; muscle histopathology; genetics; translational medicine
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Special Issue Information

Dear Colleagues,

Inherited and acquired cardiomyopathies are associated with progressive heart failure, and are a major cause of global morbidity and mortality, while skeletal myopathies are a heterogeneous group of genetic and acquired of disorders, characterized by muscle weakness and atrophy, often leading to disability, respiratory insufficiency, paralysis, and premature death. Thus, cardiac and skeletal muscle disorders significantly reduce quality of life and lifespan and have an enormous social, emotional, and economic impact. Currently, there are only few approved therapies for treating myopathies, while multidisciplinary standard of care, including respiratory, nutritional, orthopedic, and physical/occupational therapies, is the gold standard of treatment. Cardiomyopathies are managed via conventional therapy, including multiple medications, implanted devices, and heart surgery, to slow, but not prevent, the progression of the disease, ignoring disease cause and subtype. Thus, there is a strong need for better, more targeted therapies that are able to substantially modify the disease trajectory or cure these disorders.

This Special Issue of Biomedicines focuses on recent advances in the elucidation of the molecular mechanisms underlying cardiac and skeletal pathologies as a basis for the development of novel therapeutic strategies. Thus, we welcome original research articles and reviews that provide new insights into the molecular mechanisms underlying cardiac and skeletal muscle disorders, including the identification of novel therapeutic targets and pre-clinical testing of potential therapeutic strategies to improve treatment and cure. Areas of interest include, but are not limited, to, the following topics:

  • The use of pre-clinical models (animal and cell-based models) to provide a better understanding of the molecular pathways that lead to the onset and progression of pathologies affecting cardiac and/or skeletal muscle;
  • The identification of novel therapeutic targets;
  • Pre-clinical testing of potential therapies to improve treatment and cure.

Dr. Marie-Louise Bang
Prof. Dr. Edoardo Malfatti
Guest Editors

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Keywords

  • cardiomyopathies
  • skeletal myopathies
  • molecular basis of cardiac and skeletal pathologies
  • pre-clinical models, including animal and cell-based models.

Published Papers (1 paper)

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Review

21 pages, 1001 KiB  
Review
Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies
by R. John Solaro, Paul H. Goldspink and Beata M. Wolska
Biomedicines 2024, 12(5), 999; https://doi.org/10.3390/biomedicines12050999 - 2 May 2024
Viewed by 783
Abstract
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 [...] Read more.
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. Full article
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