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Sarcomeric Proteins in Health and Disease 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: 20 September 2024 | Viewed by 4445

Special Issue Editor


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Guest Editor
BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL 60616, USA
Interests: biophysics of muscle contraction; non-crystalline X-ray diffraction; synchrotron radiation instrumentation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues “Sarcomeric Proteins in Health and Disease” and “Sarcomeric Proteins in Health and Disease 2.0”.

Many inherited diseases in skeletal and cardiac muscle have their origin in mutations in sarcomeric proteins. Developing rational therapeutic strategies will require a detailed understanding of the normal structure and function of the proteins that comprise the sarcomere, as well as how these structures and functions are altered in disease.

The aim of the present Special Issue is to bring together reviews and original papers on the structure and function of specific components of the sarcomere as they relate to overall contractile function and its regulation in normal and diseased muscle tissue. Historically, the focus in molecular biophysical studies on muscle contraction has been on actin–myosin interaction.

This Special Issue is intended to be an opportunity to explore other aspects of sarcomere structure and function. These could include topics such as (1) the elastic properties of sarcomeric proteins and their role in regulation, (2) the structural dynamics of the Z-lines and M-lines, (3) sarcomeric structural proteins and cell signaling pathways, and (4) the regulation of the turnover of sarcomeric proteins. This list is not intended to be exclusive. Any of these topics could include the investigation and discussion of mutations and post-translational modifications that alter protein structure in addition to either normal or pathological function.

Prof. Dr. Thomas C. Irving
Guest Editor

Manuscript Submission Information

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Published Papers (3 papers)

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Research

22 pages, 7734 KiB  
Article
Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2
by Michelle Rodriguez Garcia, Jeffrey Schmeckpeper, Maicon Landim-Vieira, Isabella Leite Coscarella, Xuan Fang, Weikang Ma, Payton A. Spran, Shengyao Yuan, Lin Qi, Aida Rahimi Kahmini, M. Benjamin Shoemaker, James B. Atkinson, Peter M. Kekenes-Huskey, Thomas C. Irving, Prescott Bryant Chase, Björn C. Knollmann and Jose Renato Pinto
Int. J. Mol. Sci. 2023, 24(19), 14572; https://doi.org/10.3390/ijms241914572 - 26 Sep 2023
Cited by 2 | Viewed by 1384
Abstract
The ACTN2 gene encodes α-actinin 2, located in the Z-disc of the sarcomeres in striated muscle. In this study, we sought to investigate the effects of an ACTN2 missense variant of unknown significance (p.A868T) on cardiac muscle structure and function. Left ventricular free [...] Read more.
The ACTN2 gene encodes α-actinin 2, located in the Z-disc of the sarcomeres in striated muscle. In this study, we sought to investigate the effects of an ACTN2 missense variant of unknown significance (p.A868T) on cardiac muscle structure and function. Left ventricular free wall samples were obtained at the time of cardiac transplantation from a heart failure patient with the ACTN2 A868T heterozygous variant. This variant is in the EF 3–4 domain known to interact with titin and α-actinin. At the ultrastructural level, ACTN2 A868T cardiac samples presented small structural changes in cardiomyocytes when compared to healthy donor samples. However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac tissue displayed higher myofilament Ca2+ sensitivity of isometric force, reduced sinusoidal stiffness, and faster rates of tension redevelopment at all Ca2+ levels. Small-angle X-ray diffraction indicated increased separation between thick and thin filaments, possibly contributing to changes in muscle kinetics. Molecular dynamics simulations indicated that while the mutation does not significantly impact the structure of α-actinin on its own, it likely alters the conformation associated with titin binding. Our results can be explained by two Z-disc mediated communication pathways: one pathway that involves α-actinin’s interaction with actin, affecting thin filament regulation, and the other pathway that involves α-actinin’s interaction with titin, affecting thick filament activation. This work establishes the role of α-actinin 2 in modulating cross-bridge kinetics and force development in the human myocardium as well as how it can be involved in the development of cardiac disease. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 3.0)
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19 pages, 4236 KiB  
Article
Matching Mechanics and Energetics of Muscle Contraction Suggests Unconventional Chemomechanical Coupling during the Actin–Myosin Interaction
by Irene Pertici, Lorenzo Bongini, Marco Caremani, Massimo Reconditi, Marco Linari, Gabriella Piazzesi, Vincenzo Lombardi and Pasquale Bianco
Int. J. Mol. Sci. 2023, 24(15), 12324; https://doi.org/10.3390/ijms241512324 - 1 Aug 2023
Cited by 1 | Viewed by 963
Abstract
The mechanical performances of the vertebrate skeletal muscle during isometric and isotonic contractions are interfaced with the corresponding energy consumptions to define the coupling between mechanical and biochemical steps in the myosin–actin energy transduction cycle. The analysis is extended to a simplified synthetic [...] Read more.
The mechanical performances of the vertebrate skeletal muscle during isometric and isotonic contractions are interfaced with the corresponding energy consumptions to define the coupling between mechanical and biochemical steps in the myosin–actin energy transduction cycle. The analysis is extended to a simplified synthetic nanomachine in which eight HMM molecules purified from fast mammalian skeletal muscle are brought to interact with an actin filament in the presence of 2 mM ATP, to assess the emergent properties of a minimum number of motors working in ensemble without the effects of both the higher hierarchical levels of striated muscle organization and other sarcomeric, regulatory and cytoskeleton proteins. A three-state model of myosin–actin interaction is able to predict the known relationships between energetics and transient and steady-state mechanical properties of fast skeletal muscle either in vivo or in vitro only under the assumption that during shortening a myosin motor can interact with two actin sites during one ATP hydrolysis cycle. Implementation of the molecular details of the model should be achieved by exploiting kinetic and structural constraints present in the transients elicited by stepwise perturbations in length or force superimposed on the isometric contraction. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 3.0)
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12 pages, 1655 KiB  
Article
EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments
by Vivek Jani, Wenjing Qian, Shengyao Yuan, Thomas Irving and Weikang Ma
Int. J. Mol. Sci. 2022, 23(23), 14517; https://doi.org/10.3390/ijms232314517 - 22 Nov 2022
Cited by 6 | Viewed by 1360
Abstract
Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics [...] Read more.
Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics that directly target contractile proteins to improve the myocardium contractility and reduce mortality. The purpose of this study is to present a proof of concept to aid in the development of muscle activators (myotropes) for augmenting the contractility in clinical heart failure. Here we use a combination of cardiomyocyte mechanics, the biochemical quantification of the ATP turnover, and small angle X-ray diffraction on a permeabilized porcine myocardium to study the mechanisms of EMD-57033 (EMD) for activating myosin. We show that EMD increases the contractility in a porcine myocardium at submaximal and systolic calcium concentrations. Biochemical assays show that EMD decreases the proportion of myosin heads in the energy sparing super-relaxed (SRX) state under relaxing conditions, which are less likely to interact with actin during contraction. Structural assays show that EMD moves the myosin heads in relaxed muscles from a structurally ordered state close to the thick filament backbone, to a disordered state closer to the actin filament, while simultaneously inducing structural changes in the troponin complex on the actin filament. The dual effects of EMD on activating myosin heads and the troponin complex provides a proof of concept for the use of small molecule muscle activators for augmenting the contractility in heart failure. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 3.0)
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