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Sarcomeric Proteins in Health and Disease 2.0
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Sarcomeric Proteins in Health and Disease 2.0

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 21187

Special Issue Editor

Prof. Dr. Thomas C. Irving

E-Mail Website
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 Issue “Sarcomeric Proteins in Health and Disease”.

Many inherited diseases in skeletal and cardiac muscle have their origin in mutations in sarcomeric proteins. Developing rationale 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 of muscle contraction has been on actin–myosin interaction.

This 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) structural dynamics of the Z-lines and M-lines, (3) sarcomeric structural proteins and cell signaling pathways, and (4) regulation of turnover of sarcomeric proteins. This list is not intended to be exclusive. Any of these topics could include investigation and discussion of mutations and post-translational modification alter protein structure and either normal or pathological function.

Prof. Dr. Thomas C. Irving
Guest Editor

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Published Papers (6 papers)

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Research

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18 pages, 2885 KiB  
Article
Contributions of Titin and Collagen to Passive Stress in Muscles from mdm Mice with a Small Deletion in Titin’s Molecular Spring
by Pabodha Hettige, Dhruv Mishra, Henk Granzier, Kiisa Nishikawa and Matthew J. Gage
Int. J. Mol. Sci. 2022, 23(16), 8858; https://doi.org/10.3390/ijms23168858 - 9 Aug 2022
Cited by 5 | Viewed by 2678
Abstract
Muscular dystrophy with myositis (mdm) is a naturally occurring mutation in the mouse Ttn gene that results in higher passive stress in muscle fibers and intact muscles compared to wild-type (WT). The goal of this study was to test whether alternative [...] Read more.
Muscular dystrophy with myositis (mdm) is a naturally occurring mutation in the mouse Ttn gene that results in higher passive stress in muscle fibers and intact muscles compared to wild-type (WT). The goal of this study was to test whether alternative splicing of titin exons occurs in mdm muscles, which contain a small deletion in the N2A-PEVK regions of titin, and to test whether splicing changes are associated with an increase in titin-based passive tension. Although higher levels of collagen have been reported previously in mdm muscles, here we demonstrate alternative splicing of titin in mdm skeletal muscle fibers. We identified Z-band, PEVK, and C-terminus Mex5 exons as splicing hotspots in mdm titin using RNA sequencing data and further reported upregulation in ECM-associated genes. We also treated skinned mdm soleus fiber bundles with trypsin, trypsin + KCl, and trypsin + KCL + KI to degrade titin. The results showed that passive stress dropped significantly more after trypsin treatment in mdm fibers (11 ± 1.6 mN/mm2) than in WT fibers (4.8 ± 1 mN/mm2; p = 0.0004). The finding that treatment with trypsin reduces titin-based passive tension more in mdm than in WT fibers supports the hypothesis that exon splicing leads to the expression of a stiffer and shorter titin isoform in mdm fibers. After titin extraction by trypsin + KCl + KI, mdm fibers (6.7 ± 1.27 mN/mm2) had significantly higher collagen-based passive stress remaining than WT fibers (2.6 ± 1.3 mN/mm2; p = 0.0014). We conclude that both titin and collagen contribute to higher passive tension of mdm muscles. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 2.0)
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15 pages, 17722 KiB  
Article
The R369 Myosin Residue within Loop 4 Is Critical for Actin Binding and Muscle Function in Drosophila
by Adriana S. Trujillo, Karen H. Hsu, Meera C. Viswanathan, Anthony Cammarato and Sanford I. Bernstein
Int. J. Mol. Sci. 2022, 23(5), 2533; https://doi.org/10.3390/ijms23052533 - 25 Feb 2022
Cited by 2 | Viewed by 2131
Abstract
The myosin molecular motor interacts with actin filaments in an ATP-dependent manner to yield muscle contraction. Myosin heavy chain residue R369 is located within loop 4 at the actin-tropomyosin interface of myosin’s upper 50 kDa subdomain. To probe the importance of R369, we [...] Read more.
The myosin molecular motor interacts with actin filaments in an ATP-dependent manner to yield muscle contraction. Myosin heavy chain residue R369 is located within loop 4 at the actin-tropomyosin interface of myosin’s upper 50 kDa subdomain. To probe the importance of R369, we introduced a histidine mutation of that residue into Drosophila myosin and implemented an integrative approach to determine effects at the biochemical, cellular, and whole organism levels. Substituting the similarly charged but bulkier histidine residue reduces maximal actin binding in vitro without affecting myosin ATPase activity. R369H mutants exhibit impaired flight ability that is dominant in heterozygotes and progressive with age in homozygotes. Indirect flight muscle ultrastructure is normal in mutant homozygotes, suggesting that assembly defects or structural deterioration of myofibrils are not causative of reduced flight. Jump ability is also reduced in homozygotes. In contrast to these skeletal muscle defects, R369H mutants show normal heart ultrastructure and function, suggesting that this residue is differentially sensitive to perturbation in different myosin isoforms or muscle types. Overall, our findings indicate that R369 is an actin binding residue that is critical for myosin function in skeletal muscles, and suggest that more severe perturbations at this residue may cause human myopathies through a similar mechanism. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 2.0)
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16 pages, 2293 KiB  
Article
Gene Transfer of Skeletal Muscle-Type Myosin Light Chain Kinase via Adeno-Associated Virus 6 Improves Muscle Functions in an Amyotrophic Lateral Sclerosis Mouse Model
by Ryohei Oya, Osamu Tsukamoto, Tatsuro Hitsumoto, Naoya Nakahara, Chisato Okamoto, Ken Matsuoka, Hisakazu Kato, Hidenori Inohara and Seiji Takashima
Int. J. Mol. Sci. 2022, 23(3), 1747; https://doi.org/10.3390/ijms23031747 - 3 Feb 2022
Cited by 2 | Viewed by 2316
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that shows progressive muscle weakness. A few treatments exist including symptomatic therapies, which can prolong survival or reduce a symptom; however, no fundamental therapies have been found. As a therapeutic strategy, enhancing muscle force is [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that shows progressive muscle weakness. A few treatments exist including symptomatic therapies, which can prolong survival or reduce a symptom; however, no fundamental therapies have been found. As a therapeutic strategy, enhancing muscle force is important for patients’ quality of life. In this study, we focused on skeletal muscle-specific myosin regulatory light chain kinase (skMLCK), which potentially enhances muscle contraction, as overexpression of skMLCK was thought to improve muscle function. The adeno-associated virus serotype 6 encoding skMLCK (AAV6/skMLCK) and eGFP (control) was produced and injected intramuscularly into the lower limbs of SOD1G37R mice, which are a familial ALS model. AAV6/skMLCK showed the successful expression of skMLCK in the muscle tissues. Although the control did not affect the muscle force in both of the WT and SOD1G37R mice, AAV6/skMLCK enhanced the twitch force of SOD1G37R mice and the tetanic force of WT and SOD1G37R mice. These results indicate that overexpression of skMLCK can enhance the tetanic force of healthy muscle as well as rescue weakened muscle function. In conclusion, the gene transfer of skMLCK has the potential to be a new therapy for ALS as well as for other neuromuscular diseases. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 2.0)
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12 pages, 1946 KiB  
Article
Increased Expression of N2BA Titin Corresponds to More Compliant Myofibrils in Athlete’s Heart
by Dalma Kellermayer, Bálint Kiss, Hedvig Tordai, Attila Oláh, Henk L. Granzier, Béla Merkely, Miklós Kellermayer and Tamás Radovits
Int. J. Mol. Sci. 2021, 22(20), 11110; https://doi.org/10.3390/ijms222011110 - 15 Oct 2021
Cited by 3 | Viewed by 2627
Abstract
Long-term exercise induces physiological cardiac adaptation, a condition referred to as athlete’s heart. Exercise tolerance is known to be associated with decreased cardiac passive stiffness. Passive stiffness of the heart muscle is determined by the giant elastic protein titin. The adult cardiac muscle [...] Read more.
Long-term exercise induces physiological cardiac adaptation, a condition referred to as athlete’s heart. Exercise tolerance is known to be associated with decreased cardiac passive stiffness. Passive stiffness of the heart muscle is determined by the giant elastic protein titin. The adult cardiac muscle contains two titin isoforms: the more compliant N2BA and the stiffer N2B. Titin-based passive stiffness may be controlled by altering the expression of the different isoforms or via post-translational modifications such as phosphorylation. Currently, there is very limited knowledge about titin’s role in cardiac adaptation during long-term exercise. Our aim was to determine the N2BA/N2B ratio and post-translational phosphorylation of titin in the left ventricle and to correlate the changes with the structure and transverse stiffness of cardiac sarcomeres in a rat model of an athlete’s heart. The athlete’s heart was induced by a 12-week-long swim-based training. In the exercised myocardium the N2BA/N2B ratio was significantly increased, Ser11878 of the PEVK domain was hypophosphorlyated, and the sarcomeric transverse elastic modulus was reduced. Thus, the reduced passive stiffness in the athlete’s heart is likely caused by a shift towards the expression of the longer cardiac titin isoform and a phosphorylation-induced softening of the PEVK domain which is manifested in a mechanical rearrangement locally, within the cardiac sarcomere. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 2.0)
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Review

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25 pages, 3704 KiB  
Review
The Mechanisms of Thin Filament Assembly and Length Regulation in Muscles
by Szilárd Szikora, Péter Görög and József Mihály
Int. J. Mol. Sci. 2022, 23(10), 5306; https://doi.org/10.3390/ijms23105306 - 10 May 2022
Cited by 11 | Viewed by 5819
Abstract
The actin containing tropomyosin and troponin decorated thin filaments form one of the crucial components of the contractile apparatus in muscles. The thin filaments are organized into densely packed lattices interdigitated with myosin-based thick filaments. The crossbridge interactions between these myofilaments drive muscle [...] Read more.
The actin containing tropomyosin and troponin decorated thin filaments form one of the crucial components of the contractile apparatus in muscles. The thin filaments are organized into densely packed lattices interdigitated with myosin-based thick filaments. The crossbridge interactions between these myofilaments drive muscle contraction, and the degree of myofilament overlap is a key factor of contractile force determination. As such, the optimal length of the thin filaments is critical for efficient activity, therefore, this parameter is precisely controlled according to the workload of a given muscle. Thin filament length is thought to be regulated by two major, but only partially understood mechanisms: it is set by (i) factors that mediate the assembly of filaments from monomers and catalyze their elongation, and (ii) by factors that specify their length and uniformity. Mutations affecting these factors can alter the length of thin filaments, and in human cases, many of them are linked to debilitating diseases such as nemaline myopathy and dilated cardiomyopathy. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 2.0)
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34 pages, 3297 KiB  
Review
Small Angle X-ray Diffraction as a Tool for Structural Characterization of Muscle Disease
by Weikang Ma and Thomas C. Irving
Int. J. Mol. Sci. 2022, 23(6), 3052; https://doi.org/10.3390/ijms23063052 - 11 Mar 2022
Cited by 31 | Viewed by 4557
Abstract
Small angle X-ray fiber diffraction is the method of choice for obtaining molecular level structural information from striated muscle fibers under hydrated physiological conditions. For many decades this technique had been used primarily for investigating basic biophysical questions regarding muscle contraction and regulation [...] Read more.
Small angle X-ray fiber diffraction is the method of choice for obtaining molecular level structural information from striated muscle fibers under hydrated physiological conditions. For many decades this technique had been used primarily for investigating basic biophysical questions regarding muscle contraction and regulation and its use confined to a relatively small group of expert practitioners. Over the last 20 years, however, X-ray diffraction has emerged as an important tool for investigating the structural consequences of cardiac and skeletal myopathies. In this review we show how simple and straightforward measurements, accessible to non-experts, can be used to extract biophysical parameters that can help explain and characterize the physiology and pathology of a given experimental system. We provide a comprehensive guide to the range of the kinds of measurements that can be made and illustrate how they have been used to provide insights into the structural basis of pathology in a comprehensive review of the literature. We also show how these kinds of measurements can inform current controversies and indicate some future directions. Full article
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease 2.0)
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