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Molecular Research on Muscle Protein and Myopathies 2.0

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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 May 2023) | Viewed by 11951

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Prof. Dr. Yurii Borovikov

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Guest Editor

Institute of Cytology, Russian Academy of Sciences, Petersburg 194064, Russia
Interests: congenital myopathy; molecular mechanisms of muscle contraction; muscle proteins; polarized microfluorimetry
Special Issues, Collections and Topics in MDPI journals

Dr. Olga Karpicheva

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Guest Editor

Institute of Cytology of the Russian Academy of Sciences, Laboratory of Molecular Basis of Cell Motility, 4 Tikhoretsky Ave., 194064 Saint Petersburg, Russia
Interests: congenital myopathies; mutations of tropomyosin; thin filament regulation; conformational rearrangements of contractile proteins; actin-myosin interaction; myosin ATPase activity; contractile dysfunction; therapeutic approaches
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Muscle contraction is based on the cyclic interaction between actin and myosin, accompanied by ATP hydrolysis in the active center of the myosin motor domain. As a result of this interaction, the myosin filaments slide relative to the actin filaments, and the muscle sarcomeres shorten. Disruption of the molecular mechanisms of actin–myosin regulation in cardiac and skeletal muscles due to mutations in muscle proteins genes is causative of severe diseases—hereditary myopathies—which have an extremely negative effect on the quality of human life. Understanding the primary causes of muscle weakness and hypotension in cardiac and skeletal muscles in hereditary myopathies is necessary for early diagnosis and prognosis of the disease and for the development of therapeutic approaches to restore muscle contractile function. The purpose of this Special Issue is to summarize new data on the functional consequences of mutant toxic proteins for the sarcomere, to elucidate the relationship between mutations and disease phenotypes, and to identify targets for action in order to correct dysfunctions in various myopathies.

Authors are invited to contribute to this Special Issue, which will publish priority studies clarifying the molecular mechanisms of dysfunctions in cardiac and skeletal myopathies.

Topics include, but are not limited to:

study of structural and functional consequences of amino acid substitutions and deletions in sarcomeric proteins (actin, myosin, tropomyosin, troponin, nebulin, cofilin) associated with various variants of myopathies;
identification of impaired protein–protein interactions in the presence of mutations in sarcomeric proteins and analysis of further pathways of contractile dysfunction in cardiac and skeletal myopathies;
identification of targets for the restoration of normal muscle function;
search and testing of potential drugs for the treatment of muscle dysfunctions.

Prof. Dr. Yurii Borovikov
Dr. Olga Karpicheva
Guest Editors

Manuscript Submission Information

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Keywords

congenital skeletal myopathy
cardiomyopathy
desease-causing mutations
muscle contraction
calcium regulation
cross-bridge cycling and kinetics
thin filament
ATPase activity
actin–myosin interaction
therapeutic approaches

Published Papers (5 papers)

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Research

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24 pages, 10575 KiB

Open AccessArticle

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents

by Olga E. Karpicheva, Stanislava V. Avrova, Andrey L. Bogdanov, Vladimir V. Sirenko, Charles S. Redwood and Yurii S. Borovikov

Int. J. Mol. Sci. 2023, 24(6), 5829; https://doi.org/10.3390/ijms24065829 - 18 Mar 2023

Cited by 1 | Viewed by 1436

Abstract

The substitution for Arg168His (R168H) in γ-tropomyosin (TPM3 gene, Tpm3.12 isoform) is associated with congenital muscle fiber type disproportion (CFTD) and muscle weakness. It is still unclear what molecular mechanisms underlie the muscle dysfunction seen in CFTD. The aim of this work was to study the effect of the R168H mutation in Tpm3.12 on the critical conformational changes that myosin, actin, troponin, and tropomyosin undergo during the ATPase cycle. We used polarized fluorescence microscopy and ghost muscle fibers containing regulated thin filaments and myosin heads (myosin subfragment-1) modified with the 1,5-IAEDANS fluorescent probe. Analysis of the data obtained revealed that a sequential interdependent conformational-functional rearrangement of tropomyosin, actin and myosin heads takes place when modeling the ATPase cycle in the presence of wild-type tropomyosin. A multistep shift of the tropomyosin strands from the outer to the inner domain of actin occurs during the transition from weak to strong binding of myosin to actin. Each tropomyosin position determines the corresponding balance between switched-on and switched-off actin monomers and between the strongly and weakly bound myosin heads. At low Ca²⁺, the R168H mutation was shown to switch some extra actin monomers on and increase the persistence length of tropomyosin, demonstrating the freezing of the R168HTpm strands close to the open position and disruption of the regulatory function of troponin. Instead of reducing the formation of strong bonds between myosin heads and F-actin, troponin activated it. However, at high Ca²⁺, troponin decreased the amount of strongly bound myosin heads instead of promoting their formation. Abnormally high sensitivity of thin filaments to Ca²⁺, inhibition of muscle fiber relaxation due to the appearance of the myosin heads strongly associated with F-actin, and distinct activation of the contractile system at submaximal concentrations of Ca²⁺ can lead to muscle inefficiency and weakness. Modulators of troponin (tirasemtiv and epigallocatechin-3-gallate) and myosin (omecamtiv mecarbil and 2,3-butanedione monoxime) have been shown to more or less attenuate the negative effects of the tropomyosin R168H mutant. Tirasemtiv and epigallocatechin-3-gallate may be used to prevent muscle dysfunction. Full article

(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies 2.0)

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18 pages, 3042 KiB

Open AccessArticle

Silencing of the Ca²⁺ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice

by Roberto Silva-Rojas, Laura Pérez-Guàrdia, Emma Lafabrie, David Moulaert, Jocelyn Laporte and Johann Böhm

Int. J. Mol. Sci. 2022, 23(13), 6968; https://doi.org/10.3390/ijms23136968 - 23 Jun 2022

Cited by 3 | Viewed by 2445

Abstract

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca²⁺ entry due to gain-of-function mutations in the Ca²⁺ sensor STIM1 or the Ca²⁺ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1^R304W/+ mice with Orai1^+/− mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1^R304W/+Orai1^+/− mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1^R304W/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1^R304W/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues. Full article

(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies 2.0)

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13 pages, 2001 KiB

Open AccessArticle

Tks5 Regulates Synaptic Podosome Formation and Stabilization of the Postsynaptic Machinery at the Neuromuscular Junction

by Marcin Pęziński, Kamila Maliszewska-Olejniczak, Patrycja Daszczuk, Paula Mazurek, Paweł Niewiadomski and Maria Jolanta Rędowicz

Int. J. Mol. Sci. 2021, 22(21), 12051; https://doi.org/10.3390/ijms222112051 - 07 Nov 2021

Cited by 3 | Viewed by 2777

Abstract

Currently, the etiology of many neuromuscular disorders remains unknown. Many of them are characterized by aberrations in the maturation of the neuromuscular junction (NMJ) postsynaptic machinery. Unfortunately, the molecular factors involved in this process are still largely unknown, which poses a great challenge for identifying potential therapeutic targets. Here, we identified Tks5 as a novel interactor of αdystrobrevin-1, which is a crucial component of the NMJ postsynaptic machinery. Tks5 has been previously shown in cancer cells to be an important regulator of actin-rich structures known as invadosomes. However, a role of this scaffold protein at a synapse has never been studied. We show that Tks5 is crucial for remodeling of the NMJ postsynaptic machinery by regulating the organization of structures similar to the invadosomes, known as synaptic podosomes. Additionally, it is involved in the maintenance of the integrity of acetylcholine receptor (AChR) clusters and regulation of their turnover. Lastly, our data indicate that these Tks5 functions may be mediated by its involvement in recruitment of actin filaments to the postsynaptic machinery. Collectively, we show for the first time that the Tks5 protein is involved in regulation of the postsynaptic machinery. Full article

(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies 2.0)

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Review

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19 pages, 1588 KiB

Open AccessReview

Altering Calcium Sensitivity in Heart Failure: A Crossroads of Disease Etiology and Therapeutic Innovation

by Nancy S. Saad, Mohammed A. Mashali, Steven J. Repas and Paul M. L. Janssen

Int. J. Mol. Sci. 2023, 24(24), 17577; https://doi.org/10.3390/ijms242417577 - 17 Dec 2023

Cited by 1 | Viewed by 943

Abstract

Heart failure (HF) presents a significant clinical challenge, with current treatments mainly easing symptoms without stopping disease progression. The targeting of calcium (Ca²⁺) regulation is emerging as a key area for innovative HF treatments that could significantly alter disease outcomes and enhance cardiac function. In this review, we aim to explore the implications of altered Ca²⁺ sensitivity, a key determinant of cardiac muscle force, in HF, including its roles during systole and diastole and its association with different HF types—HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). We further highlight the role of the two rate constants k_on (Ca²⁺ binding to Troponin C) and k_off (its dissociation) to fully comprehend how changes in Ca²⁺ sensitivity impact heart function. Additionally, we examine how increased Ca²⁺ sensitivity, while boosting systolic function, also presents diastolic risks, potentially leading to arrhythmias and sudden cardiac death. This suggests that strategies aimed at moderating myofilament Ca²⁺ sensitivity could revolutionize anti-arrhythmic approaches, reshaping the HF treatment landscape. In conclusion, we emphasize the need for precision in therapeutic approaches targeting Ca²⁺ sensitivity and call for comprehensive research into the complex interactions between Ca²⁺ regulation, myofilament sensitivity, and their clinical manifestations in HF. Full article

(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies 2.0)

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12 pages, 274 KiB

Open AccessReview

Recent Findings Related to Cardiomyopathy and Genetics

by Takanobu Yamada and Seitaro Nomura

Int. J. Mol. Sci. 2021, 22(22), 12522; https://doi.org/10.3390/ijms222212522 - 20 Nov 2021

Cited by 22 | Viewed by 3454

Abstract

With the development and advancement of next-generation sequencing (NGS), genetic analysis is becoming more accessible. High-throughput genetic studies using NGS have contributed to unraveling the association between cardiomyopathy and genetic background, as is the case with many other diseases. Rare variants have been shown to play major roles in the pathogenesis of cardiomyopathy, which was empirically recognized as a monogenic disease, and it has been elucidated that the clinical course of cardiomyopathy varies depending on the causative genes. These findings were not limited to dilated and hypertrophic cardiomyopathy; similar trends were reported one after another for peripartum cardiomyopathy (PPCM), cancer therapy-related cardiac dysfunction (CTRCD), and alcoholic cardiomyopathy (ACM). In addition, as the association between clinical phenotypes and the causative genes becomes clearer, progress is being made in elucidating the mechanisms and developing novel therapeutic agents. Recently, it has been suggested that not only rare variants but also common variants contribute to the development of cardiomyopathy. Cardiomyopathy and genetics are approaching a new era, which is summarized here in this overview. Full article

(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies 2.0)

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