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Sarcomere Function in Health and Disease
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Sarcomere Function in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 32982

Special Issue Editors

Dr. Julien Ochala

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
Interests: muscle; myopathy; sarcomere; exercise; ageing
Dr. Marko Usaj

E-Mail Website
Guest Editor
Department Chemistry Biomedical Sciences, Linnaeus University, SE-39182 Kalmar, Sweden
Interests: myosin; actomyosin; gelsolin; contracting muscle; enzyme kinetics; myosin mitochondrial transport; protein expression and purification; single molecule biophysics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are launching a Special Issue focusing on muscle cell contractility. Indeed, one very important function of muscle cells is producing a force sufficient to allow for contraction. Such contraction requires the coordinated action of well-structured proteins named sarcomeric proteins.

As the exact function of these sarcomeric proteins (and how they interact with neighbouring molecules) to allow for muscle cell contraction is only partially known, we seek original research papers and review articles on this topic. We also hope to receive articles that better explain how these sarcomeric proteins can be dysfunctional in the context of muscle diseases.

Dr. Julien Ochala
Dr. Marko Usaj
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • myosin
  • actin
  • titin
  • z-disc
  • m-line
  • skeletal muscle
  • heart
  • contraction
  • myopathy
  • muscular dystrophy

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Published Papers (7 papers)

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Research

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17 pages, 3241 KiB  
Article
Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits
by Johan Lindqvist, Justin Kolb, Josine de Winter, Paola Tonino, Zaynab Hourani, Siegfried Labeit, Coen Ottenheijm and Henk Granzier
Int. J. Mol. Sci. 2022, 23(15), 8113; https://doi.org/10.3390/ijms23158113 - 23 Jul 2022
Cited by 3 | Viewed by 2318
Abstract
Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common [...] Read more.
Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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16 pages, 2202 KiB  
Article
Effect of Active Lengthening and Shortening on Small-Angle X-ray Reflections in Skinned Skeletal Muscle Fibres
by Venus Joumaa, Ian C. Smith, Atsuki Fukutani, Timothy R. Leonard, Weikang Ma, Srboljub M. Mijailovich, Thomas C. Irving and Walter Herzog
Int. J. Mol. Sci. 2021, 22(16), 8526; https://doi.org/10.3390/ijms22168526 - 8 Aug 2021
Cited by 10 | Viewed by 2854
Abstract
Our purpose was to use small-angle X-ray diffraction to investigate the structural changes within sarcomeres at steady-state isometric contraction following active lengthening and shortening, compared to purely isometric contractions performed at the same final lengths. We examined force, stiffness, and the 1,0 and [...] Read more.
Our purpose was to use small-angle X-ray diffraction to investigate the structural changes within sarcomeres at steady-state isometric contraction following active lengthening and shortening, compared to purely isometric contractions performed at the same final lengths. We examined force, stiffness, and the 1,0 and 1,1 equatorial and M3 and M6 meridional reflections in skinned rabbit psoas bundles, at steady-state isometric contraction following active lengthening to a sarcomere length of 3.0 µm (15.4% initial bundle length at 7.7% bundle length/s), and active shortening to a sarcomere length of 2.6 µm (15.4% bundle length at 7.7% bundle length/s), and during purely isometric reference contractions at the corresponding sarcomere lengths. Compared to the reference contraction, the isometric contraction after active lengthening was associated with an increase in force (i.e., residual force enhancement) and M3 spacing, no change in stiffness and the intensity ratio I1,1/I1,0, and decreased lattice spacing and M3 intensity. Compared to the reference contraction, the isometric contraction after active shortening resulted in decreased force, stiffness, I1,1/I1,0, M3 and M6 spacings, and M3 intensity. This suggests that residual force enhancement is achieved without an increase in the proportion of attached cross-bridges, and that force depression is accompanied by a decrease in the proportion of attached cross-bridges. Furthermore, the steady-state isometric contraction following active lengthening and shortening is accompanied by an increase in cross-bridge dispersion and/or a change in the cross-bridge conformation compared to the reference contractions. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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18 pages, 3355 KiB  
Article
The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics
by Elizabeth Vafiadaki, Demetrios A. Arvanitis, Aristides G. Eliopoulos, Evangelia G. Kranias and Despina Sanoudou
Int. J. Mol. Sci. 2020, 21(24), 9572; https://doi.org/10.3390/ijms21249572 - 16 Dec 2020
Cited by 9 | Viewed by 2519
Abstract
The cytoskeleton has a primary role in cardiomyocyte function, including the response to mechanical stimuli and injury. The small heat shock protein 20 (Hsp20) conveys protective effects in cardiac muscle that are linked to serine-16 (Ser16) Hsp20 phosphorylation by stress-induced PKA, but the [...] Read more.
The cytoskeleton has a primary role in cardiomyocyte function, including the response to mechanical stimuli and injury. The small heat shock protein 20 (Hsp20) conveys protective effects in cardiac muscle that are linked to serine-16 (Ser16) Hsp20 phosphorylation by stress-induced PKA, but the link between Hsp20 and the cytoskeleton remains poorly understood. Herein, we demonstrate a physical and functional interaction of Hsp20 with the cytoskeletal protein 14-3-3. We show that, upon phosphorylation at Ser16, Hsp20 translocates from the cytosol to the cytoskeleton where it binds to 14-3-3. This leads to dissociation of 14-3-3 from the F-actin depolymerization regulator cofilin-2 (CFL2) and enhanced F-actin depolymerization. Importantly, we demonstrate that the P20L Hsp20 mutation associated with dilated cardiomyopathy exhibits reduced physical interaction with 14-3-3 due to diminished Ser16 phosphorylation, with subsequent failure to translocate to the cytoskeleton and inability to disassemble the 14-3-3/CFL2 complex. The topological sequestration of Hsp20 P20L ultimately results in impaired regulation of F-actin dynamics, an effect implicated in loss of cytoskeletal integrity and amelioration of the cardioprotective functions of Hsp20. These findings underscore the significance of Hsp20 phosphorylation in the regulation of actin cytoskeleton dynamics, with important implications in cardiac muscle physiology and pathophysiology. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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Review

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44 pages, 4809 KiB  
Review
Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy
by Marko Ušaj, Luisa Moretto and Alf Månsson
Int. J. Mol. Sci. 2022, 23(4), 2195; https://doi.org/10.3390/ijms23042195 - 16 Feb 2022
Cited by 12 | Viewed by 4440
Abstract
Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at [...] Read more.
Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank–Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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22 pages, 23284 KiB  
Review
Cardiomyocyte Dysfunction in Inherited Cardiomyopathies
by Roua Hassoun, Heidi Budde, Andreas Mügge and Nazha Hamdani
Int. J. Mol. Sci. 2021, 22(20), 11154; https://doi.org/10.3390/ijms222011154 - 15 Oct 2021
Cited by 4 | Viewed by 5869
Abstract
Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to [...] Read more.
Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to outline the functional consequences of the major inherited cardiomyopathies in terms of myocardial contraction and kinetics, and to highlight the structural and functional alterations in some sarcomeric variants that have been demonstrated to be involved in the pathogenesis of the inherited cardiomyopathies. A particular focus was made on mutation-induced alterations in cardiomyocyte mechanics. Since no disease-specific treatments for familial cardiomyopathies exist, several novel agents have been developed to modulate sarcomere contractility. Understanding the molecular basis of the disease opens new avenues for the development of new therapies. Furthermore, the earlier the awareness of the genetic defect, the better the clinical prognostication would be for patients and the better the prevention of development of the disease. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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30 pages, 1990 KiB  
Review
Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases
by Khulud Alsulami and Steven Marston
Int. J. Mol. Sci. 2020, 21(24), 9599; https://doi.org/10.3390/ijms21249599 - 16 Dec 2020
Cited by 43 | Viewed by 7075
Abstract
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the [...] Read more.
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as “recouplers” was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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Graphical abstract

58 pages, 4121 KiB  
Review
The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease
by Jordan Blondelle, Andrea Biju and Stephan Lange
Int. J. Mol. Sci. 2020, 21(21), 7936; https://doi.org/10.3390/ijms21217936 - 26 Oct 2020
Cited by 12 | Viewed by 6528
Abstract
The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are [...] Read more.
The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are degraded by the ubiquitin–proteasome system (UPS). The UPS involves a number of enzymes, including E3-ligases, which tightly control which protein substrates are marked for degradation by the proteasome. Recent data reveal that E3-ligases of the cullin family play more diverse and crucial roles in cross striated muscles than previously anticipated. This review highlights some of the findings on the multifaceted functions of cullin-RING E3-ligases, their substrate adapters, muscle protein substrates, and regulatory proteins, such as the Cop9 signalosome, for the development of cross striated muscles, and their roles in the etiology of myopathies. Full article
(This article belongs to the Special Issue Sarcomere Function in Health and Disease)
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