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Sarcomeric Proteins in Health and Disease: 3rd Edition
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Sarcomeric Proteins in Health and Disease: 3rd Edition

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: closed (20 April 2025) | Viewed by 14055

Special Issue Editor

Prof. Dr. Thomas C. Irving

E-Mail Website
Guest Editor
Department of Biological Sciences, Illinois Institute of Technology, Chicago, IL, 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

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Published Papers (7 papers)

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Research

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25 pages, 6067 KiB  
Article
Early-Stage Alcoholic Cardiomyopathy Highlighted by Metabolic Remodeling, Oxidative Stress, and Cardiac Myosin Dysfunction in Male Rats
by David V. Rasicci, Jinghua Ge, Adrien P. Chen, Neil B. Wood, Skylar M. L. Bodt, Allyson L. Toro, Alexandra Evans, Omid Golestanian, Md Shahrier Amin, Anne Pruznak, Nelli Mnatsakanyan, Yuval Silberman, Michael D. Dennis, Michael J. Previs, Charles H. Lang and Christopher M. Yengo
Int. J. Mol. Sci. 2025, 26(14), 6766; https://doi.org/10.3390/ijms26146766 - 15 Jul 2025
Viewed by 313
Abstract
Chronic ethanol use can lead to alcoholic cardiomyopathy (ACM), while the impact on the molecular and cellular aspects of the myocardium is unclear. Accordingly, male Sprague-Dawley rats were exposed to an ethanol-containing diet for 16 weeks and compared with a control group that [...] Read more.
Chronic ethanol use can lead to alcoholic cardiomyopathy (ACM), while the impact on the molecular and cellular aspects of the myocardium is unclear. Accordingly, male Sprague-Dawley rats were exposed to an ethanol-containing diet for 16 weeks and compared with a control group that was fed an isocaloric diet. Histological measurements from H&E slides revealed no significant differences in cell size. A proteomic approach revealed that alcohol exposure leads to enhanced mitochondrial lipid metabolism, and electron microscopy revealed impairments in mitochondrial morphology/density. Cardiac myosin purified from the hearts of ethanol-exposed animals demonstrated a 15% reduction in high-salt ATPase activity, with no significant changes in the in vitro motility and low-salt ATPase or formation of the super-relaxed (SRX) state. A protein carbonyl assay indicated a 20% increase in carbonyl incorporation, suggesting that alcohol may impact cardiac myosin through oxidative stress mechanisms. In vitro oxidation of healthy cardiac myosin revealed a dramatic decline in ATPase activity and in vitro motility, demonstrating a link between myosin protein oxidation and myosin mechanochemistry. Collectively, this study suggests alcohol-induced metabolic remodeling may be the initial insult that eventually leads to defects in the contractile machinery in the myocardium of ACM hearts. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease: 3rd Edition)
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12 pages, 1281 KiB  
Article
The N-Terminal Mutations of cMyBP-C Affect Calcium Regulation, Kinetics, and Force of Muscle Contraction
by Salavat R. Nabiev, Galina V. Kopylova, Victoria V. Nefedova, Alexander M. Matyushenko, Daniil V. Shchepkin and Sergey Y. Bershitsky
Int. J. Mol. Sci. 2024, 25(24), 13405; https://doi.org/10.3390/ijms252413405 - 13 Dec 2024
Viewed by 1427
Abstract
The cardiac myosin binding protein-C (cMyBP-C) regulates cross-bridge formation and controls the duration of systole and diastole at the whole heart level. As known, mutations in cMyBP-C increase the cross-bridge number and rate of their cycling, hypercontractility, and myocardial hypertrophy. We investigated the [...] Read more.
The cardiac myosin binding protein-C (cMyBP-C) regulates cross-bridge formation and controls the duration of systole and diastole at the whole heart level. As known, mutations in cMyBP-C increase the cross-bridge number and rate of their cycling, hypercontractility, and myocardial hypertrophy. We investigated the effects of the mutations D75N and P161S of cMyBP-C related to hypertrophic cardiomyopathy on the mechanism of force generation in isolated slow skeletal muscle fibers. The mutation D75N slowed the kinetics of force development but did not affect the relaxation rate. The mutation P161S slowed both the relaxation and force development. The mutation D75N increased the calcium sensitivity of force, and the mutation P161S decreased it. The mutation D75N decreased the maximal isometric tension and increased the tension and stiffness at low calcium. Both mutations studied disrupt the calcium regulation of contractile force and affect the kinetics of its development and thus may impair cardiac diastolic function and cause myocardial hypertrophy. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease: 3rd Edition)
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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 4 | Viewed by 2813
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: 3rd Edition)
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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 2 | Viewed by 2135
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: 3rd Edition)
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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 8 | Viewed by 2198
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: 3rd Edition)
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Review

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25 pages, 3051 KiB  
Review
Alcohol Alters Skeletal Muscle Bioenergetic Function: A Scoping Review
by Matthew R. DiLeo, Rylea E. Hall, Heather L. Vellers, Chelsea L. Daniels and Danielle E. Levitt
Int. J. Mol. Sci. 2024, 25(22), 12280; https://doi.org/10.3390/ijms252212280 - 15 Nov 2024
Cited by 4 | Viewed by 3166
Abstract
Bioenergetic pathways uniquely support sarcomere function which, in turn, helps to maintain functional skeletal muscle (SKM) mass. Emerging evidence supports alcohol (EtOH)-induced bioenergetic impairments in SKM and muscle precursor cells. We performed a scoping review to synthesize existing evidence regarding the effects of [...] Read more.
Bioenergetic pathways uniquely support sarcomere function which, in turn, helps to maintain functional skeletal muscle (SKM) mass. Emerging evidence supports alcohol (EtOH)-induced bioenergetic impairments in SKM and muscle precursor cells. We performed a scoping review to synthesize existing evidence regarding the effects of EtOH on SKM bioenergetics. Eligible articles from six databases were identified, and titles, abstracts, and full texts for potentially relevant articles were screened against inclusion criteria. Through the search, we identified 555 unique articles, and 21 met inclusion criteria. Three studies investigated EtOH effects on the adenosine triphosphate (ATP)-phosphocreatine (PCr) system, twelve investigated EtOH effects on glycolytic metabolism, and seventeen investigated EtOH effects on mitochondrial metabolism. Despite increased ATP-PCr system reliance, EtOH led to an overall decrease in bioenergetic function through decreased expression and activity of glycolytic and mitochondrial pathway components. However, effects varied depending on the EtOH dose and duration, model system, and sample type. The results detail the EtOH-induced shifts in energy metabolism, which may adversely affect sarcomere function and contribute to myopathy. These findings should be used to develop targeted interventions that improve SKM bioenergetic function, and thus sarcomere function, in people with Alcohol Use Disorder (AUD). Key areas in need of further investigation are also identified. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease: 3rd Edition)
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Other

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14 pages, 2171 KiB  
Brief Report
Pulsatile Myofilament Activity in Myotrem Myopathy Associated with Myogenic Tremor
by Jennifer Megan Mariano, Laurin M. Hanft, Suhan Cho, Christopher W. Ward, Kerry S. McDonald and Aikaterini Kontrogianni-Konstantopoulos
Int. J. Mol. Sci. 2025, 26(11), 5252; https://doi.org/10.3390/ijms26115252 - 30 May 2025
Viewed by 514
Abstract
Myosin-binding protein C (MyBP-C) comprises a family of myofilament proteins that maintain sarcomeric structure and regulate actomyosin crossbridge cycling. Pathogenic variants in MYBPC1, the gene encoding the slow skeletal isoform (sMyBP-C), lead to a dominant congenital myopathy, termed Myotrem, characterized by muscle [...] Read more.
Myosin-binding protein C (MyBP-C) comprises a family of myofilament proteins that maintain sarcomeric structure and regulate actomyosin crossbridge cycling. Pathogenic variants in MYBPC1, the gene encoding the slow skeletal isoform (sMyBP-C), lead to a dominant congenital myopathy, termed Myotrem, characterized by muscle weakness, hypotonia, and a distinctive tremor of myogenic origin, in the absence of neuropathy. However, the molecular mechanism(s) of myogenic tremorgenesis is largely unknown. One potential mechanism is aberrant myofilament stretch activation, which is defined as a delayed increase in force after a rapid stretch. We utilized the Myotrem murine model harboring the pathogenic MYBPC1 E248K variant to test the hypothesis that stretch activation is augmented in permeabilized Myotrem E248K soleus fibers. We found that stretch activation was significantly increased in E248K soleus muscle fibers. Interestingly, once submaximally Ca2+ activated, a subpopulation of slow-twitch E248K fibers exhibited spontaneous pulsatile sarcomere oscillations. This pulsing behavior generated a sinusoidal waveform pattern in sarcomere length, which often persisted on a timescale of minutes. These results align with sMyBP-C as key regulator of the synchronous activation of myofilaments by dampening both spontaneous oscillatory activity and stretch-dependent activation. We propose that the presence of sMyBP-C-E248K disrupts this regulation, thereby driving pathogenic myogenic tremors. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease: 3rd Edition)
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