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Molecular Research on Muscle Protein and Myopathies

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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 (29 July 2021) | Viewed by 28090

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Special Issue Editors

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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Co-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.

Dr. Yurii Borovikov
Prof. Dr. Yurii Borovikov
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 (10 papers)

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Editorial

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4 pages, 188 KiB

Open AccessEditorial

Molecular Research on Muscle Protein and Myopathies

by Olga Karpicheva

Int. J. Mol. Sci. 2022, 23(13), 7098; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137098 - 26 Jun 2022

Viewed by 994

Abstract

This Special Issue highlights new data on the molecular mechanisms of muscle functioning under normal conditions and cellular dysfunctions [...] Full article

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

Research

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13 pages, 3519 KiB

Open AccessArticle

Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation

by Hongyi Zhou, Huabo Su and Weiqin Chen

Int. J. Mol. Sci. 2021, 22(17), 9509; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179509 - 01 Sep 2021

Cited by 6 | Viewed by 2657

Abstract

As the largest tissue in the body, skeletal muscle has multiple functions in movement and energy metabolism. Skeletal myogenesis is controlled by a transcriptional cascade including a set of muscle regulatory factors (MRFs) that includes Myogenic Differentiation 1 (MYOD1), Myocyte Enhancer Factor 2 (MEF2), and Myogenin (MYOG), which direct the fusion of myogenic myoblasts into multinucleated myotubes. Neddylation is a posttranslational modification that covalently conjugates ubiquitin-like NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to protein targets. Inhibition of neddylation impairs muscle differentiation; however, the underlying molecular mechanisms remain less explored. Here, we report that neddylation is temporally regulated during myoblast differentiation. Inhibition of neddylation through pharmacological blockade using MLN4924 (Pevonedistat) or genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1), a subunit of the E1 neddylation-activating enzyme, blocks terminal myoblast differentiation partially through repressing MYOG expression. Mechanistically, we found that neddylation deficiency enhances the mRNA and protein expressions of class IIa histone deacetylases 4 and 5 (HDAC4 and 5) and prevents the downregulation and nuclear export of class III HDAC (NAD-Dependent Protein Deacetylase Sirtuin-1, SIRT1), all of which have been shown to repress MYOD1-mediated MYOG transcriptional activation. Together, our findings for the first time identify the crucial role of neddylation in mediating class IIa and III HDAC co-repressors to control myogenic program and provide new insights into the mechanisms of muscle disease and regeneration. Full article

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

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26 pages, 69127 KiB

Open AccessArticle

Drebrin Regulates Acetylcholine Receptor Clustering and Organization of Microtubules at the Postsynaptic Machinery

by Paloma Alvarez-Suarez, Natalia Nowak, Anna Protasiuk-Filipunas, Hiroyuki Yamazaki, Tomasz J. Prószyński and Marta Gawor

Int. J. Mol. Sci. 2021, 22(17), 9387; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179387 - 30 Aug 2021

Cited by 3 | Viewed by 3067

Abstract

Proper muscle function depends on the neuromuscular junctions (NMJs), which mature postnatally to complex “pretzel-like” structures, allowing for effective synaptic transmission. Postsynaptic acetylcholine receptors (AChRs) at NMJs are anchored in the actin cytoskeleton and clustered by the scaffold protein rapsyn, recruiting various actin-organizing proteins. Mechanisms driving the maturation of the postsynaptic machinery and regulating rapsyn interactions with the cytoskeleton are still poorly understood. Drebrin is an actin and microtubule cross-linker essential for the functioning of the synapses in the brain, but its role at NMJs remains elusive. We used immunohistochemistry, RNA interference, drebrin inhibitor 3,5-bis-trifluoromethyl pyrazole (BTP2) and co-immunopreciptation to explore the role of this protein at the postsynaptic machinery. We identify drebrin as a postsynaptic protein colocalizing with the AChRs both in vitro and in vivo. We also show that drebrin is enriched at synaptic podosomes. Downregulation of drebrin or blocking its interaction with actin in cultured myotubes impairs the organization of AChR clusters and the cluster-associated microtubule network. Finally, we demonstrate that drebrin interacts with rapsyn and a drebrin interactor, plus-end-tracking protein EB3. Our results reveal an interplay between drebrin and cluster-stabilizing machinery involving rapsyn, actin cytoskeleton, and microtubules. Full article

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

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24 pages, 6584 KiB

Open AccessArticle

Molecular Mechanisms of the Deregulation of Muscle Contraction Induced by the R90P Mutation in Tpm3.12 and the Weakening of This Effect by BDM and W7

by Yurii S. Borovikov, Daria D. Andreeva, Stanislava V. Avrova, Vladimir V. Sirenko, Armen O. Simonyan, Charles S. Redwood and Olga E. Karpicheva

Int. J. Mol. Sci. 2021, 22(12), 6318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126318 - 12 Jun 2021

Cited by 7 | Viewed by 1776

Abstract

Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca²⁺-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin’s ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca²⁺. These changes in the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca²⁺-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca²⁺-dependent movement and the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility. Full article

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

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15 pages, 15213 KiB

Open AccessArticle

Mutations Q93H and E97K in TPM2 Disrupt Ca-Dependent Regulation of Actin Filaments

by Małgorzata Śliwinska, Katarzyna Robaszkiewicz, Piotr Wasąg and Joanna Moraczewska

Int. J. Mol. Sci. 2021, 22(8), 4036; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084036 - 14 Apr 2021

Cited by 7 | Viewed by 1748

Abstract

Tropomyosin is a two-chain coiled coil protein, which together with the troponin complex controls interactions of actin with myosin in a Ca²⁺-dependent manner. In fast skeletal muscle, the contractile actin filaments are regulated by tropomyosin isoforms Tpm1.1 and Tpm2.2, which form homo- and heterodimers. Mutations in the TPM2 gene encoding isoform Tpm2.2 are linked to distal arthrogryposis and congenital myopathy—skeletal muscle diseases characterized by hyper- and hypocontractile phenotypes, respectively. In this work, in vitro functional assays were used to elucidate the molecular mechanisms of mutations Q93H and E97K in TPM2. Both mutations tended to decrease actin affinity of homo-and heterodimers in the absence and presence of troponin and Ca²⁺, although the effect of Q93H was stronger. Changes in susceptibility of tropomyosin to trypsin digestion suggested that the mutations diversified dynamics of tropomyosin homo- and heterodimers on the filament. The presence of Q93H in homo- and heterodimers strongly decreased activation of the actomyosin ATPase and reduced sensitivity of the thin filament to [Ca²⁺]. In contrast, the presence of E97K caused hyperactivation of the ATPase and increased sensitivity to [Ca²⁺]. In conclusion, the hypo- and hypercontractile phenotypes associated with mutations Q93H and E97K in Tpm2.2 are caused by defects in Ca²⁺-dependent regulation of actin–myosin interactions. Full article

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

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17 pages, 1664 KiB

Open AccessArticle

The Effects of Muscle Cell Aging on Myogenesis

by Athanasios Moustogiannis, Anastassios Philippou, Orjona Taso, Evangelos Zevolis, Maria Pappa, Antonios Chatzigeorgiou and Michael Koutsilieris

Int. J. Mol. Sci. 2021, 22(7), 3721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073721 - 02 Apr 2021

Cited by 22 | Viewed by 4738

Abstract

The process of myogenesis gradually deteriorates as the skeletal muscle ages, contributing to muscle mass loss. The aim of this study is to investigate the effect of senescence/aging on skeletal myogenesis, in vitro. A model of multiple cell divisions of C2C12 myoblasts was used to replicate cell senescence. Control and aged myoblasts were investigated during myogenesis, i.e., at days 0, 2, and 6of differentiation. SA-β-gal activity and comet assay were used as markers of aging and DNA damage. Flow cytometry was performed to characterize potential differences in cell cycle between control and aged cells. Alterations in the mRNA and/or protein expression of myogenic regulatory factors (MRFs), IGF-1 isoforms, apoptotic, atrophy, inflammatory, metabolic and aging-related factors were evaluated. Compared with the control cells, aged myoblasts exhibited G0/G1 cell cycle arrest, DNA damage, increased SA-β-gal activity, and increased expression of aging-related factors p16 and p21 during differentiation. Moreover, aged myoblasts showed a reduction in the expression of MRFs and metabolic/anabolic factors, along with an increased expression of apoptotic, atrophy and inflammatory factors. A diminished differentiation capacity characterized the aged myoblasts which, in combination with the induction of apoptotic and atrophy factors, indicated a disrupted myogenic lineage in the senescent muscle cells. Full article

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

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19 pages, 3831 KiB

Open AccessArticle

Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

by Joanna Gruszczynska-Biegala, Andrzej Stefan, Andrzej A. Kasprzak, Piotr Dobryszycki, Sofia Khaitlina and Hanna Strzelecka-Gołaszewska

Int. J. Mol. Sci. 2021, 22(5), 2327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052327 - 26 Feb 2021

Cited by 3 | Viewed by 1781

Abstract

Formation of stable actin filaments, critically important for actin functions, is determined by the ionic strength of the solution. However, not much is known about the elements of the actin fold involved in ionic-strength-dependent filament stabilization. In this work, F-actin was destabilized by Cu²⁺ binding to Cys374, and the effects of solvent conditions on the dynamic properties of F-actin were correlated with the involvement of Segment 227-235 in filament stabilization. The results of our work show that the presence of Mg²⁺ at the high-affinity cation binding site of Cu-modified actin polymerized with MgCl₂ strongly enhances the rate of filament subunit exchange and promotes the filament instability. In the presence of 0.1 M KCl, the filament subunit exchange was 2–3-fold lower than that in the MgCl₂-polymerized F-actin. This effect correlates with the reduced accessibility of the D-loop and Segment 227-235 on opposite filament strands, consistent with an ionic-strength-dependent conformational change that modulates involvement of Segment 227-235 in stabilization of the intermonomer interface. KCl may restrict the mobility of the α-helix encompassing part of Segment 227-235 and/or be bound to Asp236 at the boundary of Segment 227-235. These results provide experimental evidence for the involvement of Segment 227-235 in salt-induced stabilization of contacts within the actin filament and suggest that they can be weakened by mutations characteristic of actin-associated myopathies. Full article

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

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16 pages, 5268 KiB

Open AccessArticle

Impact of A134 and E218 Amino Acid Residues of Tropomyosin on Its Flexibility and Function

by Marina A. Marchenko, Victoria V. Nefedova, Daria S. Yampolskaya, Galina V. Kopylova, Daniil V. Shchepkin, Sergey Y. Bershitsky, Natalia A. Koubassova, Andrey K. Tsaturyan, Dmitrii I. Levitsky and Alexander M. Matyushenko

Int. J. Mol. Sci. 2020, 21(22), 8720; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228720 - 18 Nov 2020

Cited by 4 | Viewed by 1821

Abstract

Tropomyosin (Tpm) is one of the major actin-binding proteins that play a crucial role in the regulation of muscle contraction. The flexibility of the Tpm molecule is believed to be vital for its functioning, although its role and significance are under discussion. We choose two sites of the Tpm molecule that presumably have high flexibility and stabilized them with the A134L or E218L substitutions. Applying differential scanning calorimetry (DSC), molecular dynamics (MD), co-sedimentation, trypsin digestion, and in vitro motility assay, we characterized the properties of Tpm molecules with these substitutions. The A134L mutation prevented proteolysis of Tpm molecule by trypsin, and both substitutions increased the thermal stability of Tpm and its bending stiffness estimated from MD simulation. None of these mutations affected the primary binding of Tpm to F-actin; still, both of them increased the thermal stability of the actin-Tpm complex and maximal sliding velocity of regulated thin filaments in vitro at a saturating Ca²⁺ concentration. However, the mutations differently affected the Ca²⁺ sensitivity of the sliding velocity and pulling force produced by myosin heads. The data suggest that both regions of instability are essential for correct regulation and fine-tuning of Ca²⁺-dependent interaction of myosin heads with F-actin. Full article

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

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15 pages, 2554 KiB

Open AccessArticle

Genomic Amplification and Functional Dependency of the Gamma Actin Gene ACTG1 in Uterine Cancer

by Camden Richter, David Mayhew, Jonathan P. Rennhack, Jonathan So, Elizabeth H. Stover, Justin H. Hwang and Danuta Szczesna-Cordary

Int. J. Mol. Sci. 2020, 21(22), 8690; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228690 - 18 Nov 2020

Cited by 14 | Viewed by 3060

Abstract

Sarcomere and cytoskeleton genes, or actomyosin genes, regulate cell biology including mechanical stress, cell motility, and cell division. While actomyosin genes are recurrently dysregulated in cancers, their oncogenic roles have not been examined in a lineage-specific fashion. In this report, we investigated dysregulation of nine sarcomeric and cytoskeletal genes across 20 cancer lineages. We found that uterine cancers harbored the highest frequencies of amplification and overexpression of the gamma actin gene, ACTG1. Each of the four subtypes of uterine cancers, mixed endometrial carcinomas, serous carcinomas, endometroid carcinomas, and carcinosarcomas harbored between 5~20% of ACTG1 gene amplification or overexpression. Clinically, patients with ACTG1 gains had a poor prognosis. ACTG1 gains showed transcriptional patterns that reflect activation of oncogenic signals, repressed response to innate immunity, or immunotherapy. Functionally, the CRISPR-CAS9 gene deletion of ACTG1 had the most robust and consistent effects in uterine cancer cells relative to 20 other lineages. Overall, we propose that ACTG1 regulates the fitness of uterine cancer cells by modulating cell-intrinsic properties and the tumor microenvironment. In summary, the ACTG1 functions relative to other actomyosin genes support the notion that it is a potential biomarker and a target gene in uterine cancer precision therapies. Full article

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

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Review

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30 pages, 2185 KiB

Open AccessReview

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

by Kirsty Wadmore, Amar J. Azad and Katja Gehmlich

Int. J. Mol. Sci. 2021, 22(6), 3058; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063058 - 17 Mar 2021

Cited by 28 | Viewed by 5238

Abstract

The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts. Full article

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

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