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Calcium Homeostasis in Skeletal Muscle Function, Plasticity and Disease

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

Deadline for manuscript submissions: closed (25 March 2024) | Viewed by 8530

Special Issue Editors


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Guest Editor
Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98., H-4002 Debrecen, Hungary
Interests: skeletal muscle; intracellular calcium; excitation contraction coupling; muscle force; myopathies; aging; antioxidants
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Co-Guest Editor
Department of Physiology, Medical Faculty, University of Debrecen, H-4002 Debrecen, Hungary
Interests: calcium signaling; skeletal muscle; excitation-contraction coupling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Whether in health or in disease, calcium as a second messenger, plays a very important role in muscle development, regeneration and function. One of these the excitation-contraction coupling, which is the progression from membrane excitation to the rise of the intracellular Ca2+ concentration to muscle contraction. Although Ca2+ is one of most widely studied ion in all type of muscle, there are several aspects which are still unclear about its role in physiological and also in pathological conditions. For example, there was a dogma that skeletal muscle can contract without external calcium. Recent studies question the truth of this statement and proved that external calcium (like store operated calcium entry, SOCE) is necessary to maintain muscle force in special physiological and in certain pathological conditions. Like any other field of human research, aging is one of the hot topic in skeletal muscle studies. However, muscle weakness can occur not only in old age but accompanying phenomenon is many myopathies and the role of Ca2+ in these processes should be clarified. Fortunately, new technological challenges and innovations on the use of calcium sensors appears time-to-time and opens new possibilities to deepen our knowledge about the role of calcium in muscle physiology.

The aim of the present special issue is to collect novel data regarding the role of calcium in the functions of skeletal muscle. We specifically encourage the submission of manuscripts presenting innovative approaches to identify novel strategies to maintain and/or improve muscle functions in aging and in myopathies.

Dr. Péter Szentesi
Prof. Dr. László Csernoch
Guest Editors

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Keywords

  • skeletal muscle
  • intracellular calcium
  • excitation contraction coupling
  • muscle force
  • myopathies
  • aging

Published Papers (5 papers)

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Research

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28 pages, 4312 KiB  
Article
The RyR1 P3528S Substitution Alters Mouse Skeletal Muscle Contractile Properties and RyR1 Ion Channel Gating
by Chris G. Thekkedam, Travis L. Dutka, Chris Van der Poel, Gaetan Burgio and Angela F. Dulhunty
Int. J. Mol. Sci. 2024, 25(1), 434; https://doi.org/10.3390/ijms25010434 - 28 Dec 2023
Viewed by 660
Abstract
The recessive Ryanodine Receptor Type 1 (RyR1) P3527S mutation causes mild muscle weakness in patients and increased resting cytoplasmic [Ca2+] in transformed lymphoblastoid cells. In the present study, we explored the cellular/molecular effects of this mutation in a mouse model of [...] Read more.
The recessive Ryanodine Receptor Type 1 (RyR1) P3527S mutation causes mild muscle weakness in patients and increased resting cytoplasmic [Ca2+] in transformed lymphoblastoid cells. In the present study, we explored the cellular/molecular effects of this mutation in a mouse model of the mutation (RyR1 P3528S). The results were obtained from 73 wild type (WT/WT), 82 heterozygous (WT/MUT) and 66 homozygous (MUT/MUT) mice with different numbers of observations in individual data sets depending on the experimental protocol. The results showed that WT/MUT and MUT/MUT mouse strength was less than that of WT/WT mice, but there was no difference between genotypes in appearance, weight, mobility or longevity. The force frequency response of extensor digitorum longus (EDL) and soleus (SOL) muscles from WT/MUT and MUT/MUT mice was shifter to higher frequencies. The specific force of EDL muscles was reduced and Ca2+ activation of skinned fibres shifted to a lower [Ca2+], with an increase in type I fibres in EDL muscles and in mixed type I/II fibres in SOL muscles. The relative activity of RyR1 channels exposed to 1 µM cytoplasmic Ca2+ was greater in WT/MUT and MUT/MUT mice than in WT/WT mice. We suggest the altered RyR1 activity due to the P2328S substitution could increase resting [Ca2+] in muscle fibres, leading to changes in fibre type and contractile properties. Full article
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19 pages, 4839 KiB  
Article
Unravelling the Effects of Syndecan-4 Knockdown on Skeletal Muscle Functions
by Mónika Sztretye, Zoltán Singlár, Nyamkhuu Ganbat, Dána Al-Gaadi, Kitti Szabó, Zoltán Márton Köhler, László Dux, Anikó Keller-Pintér, László Csernoch and Péter Szentesi
Int. J. Mol. Sci. 2023, 24(8), 6933; https://doi.org/10.3390/ijms24086933 - 08 Apr 2023
Cited by 3 | Viewed by 1452
Abstract
The remodelling of the extracellular matrix plays an important role in skeletal muscle development and regeneration. Syndecan-4 is a cell surface proteoglycan crucial for muscle differentiation. Syndecan-4−/− mice have been reported to be unable to regenerate following muscle damage. To investigate the [...] Read more.
The remodelling of the extracellular matrix plays an important role in skeletal muscle development and regeneration. Syndecan-4 is a cell surface proteoglycan crucial for muscle differentiation. Syndecan-4−/− mice have been reported to be unable to regenerate following muscle damage. To investigate the consequences of the decreased expression of Syndecan-4, we have studied the in vivo and in vitro muscle performance and the excitation–contraction coupling machinery in young and aged Syndecan-4+/− (SDC4) mice. In vivo grip force was decreased significantly as well as the average and maximal speed of voluntary running in SDC4 mice, regardless of their age. The maximal in vitro twitch force was reduced in both EDL and soleus muscles from young and aged SDC4 mice. Ca2+ release from the sarcoplasmic reticulum decreased significantly in the FDB fibres of young SDC4 mice, while its voltage dependence was unchanged regardless of age. These findings were present in muscles from young and aged mice as well. On C2C12 murine skeletal muscle cells, we have also found altered calcium homeostasis upon Syndecan-4 silencing. The decreased expression of Syndecan-4 leads to reduced skeletal muscle performance in mice and altered motility in C2C12 myoblasts via altered calcium homeostasis. The altered muscle force performance develops at an early age and is maintained throughout the life course of the animal until old age. Full article
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18 pages, 14689 KiB  
Article
Searching for Mechanisms Underlying the Assembly of Calcium Entry Units: The Role of Temperature and pH
by Barbara Girolami, Matteo Serano, Alessia Di Fonso, Cecilia Paolini, Laura Pietrangelo and Feliciano Protasi
Int. J. Mol. Sci. 2023, 24(6), 5328; https://doi.org/10.3390/ijms24065328 - 10 Mar 2023
Cited by 1 | Viewed by 1274
Abstract
Store-operated Ca2+ entry (SOCE) is a mechanism that allows muscle fibers to recover external Ca2+, which first enters the cytoplasm and then, via SERCA pump, also refills the depleted intracellular stores (i.e., the sarcoplasmic reticulum, SR). We recently discovered that [...] Read more.
Store-operated Ca2+ entry (SOCE) is a mechanism that allows muscle fibers to recover external Ca2+, which first enters the cytoplasm and then, via SERCA pump, also refills the depleted intracellular stores (i.e., the sarcoplasmic reticulum, SR). We recently discovered that SOCE is mediated by Calcium Entry Units (CEUs), intracellular junctions formed by: (i) SR stacks containing STIM1; and (ii) I-band extensions of the transverse tubule (TT) containing Orai1. The number and size of CEUs increase during prolonged muscle activity, though the mechanisms underlying exercise-dependent formation of new CEUs remain to be elucidated. Here, we first subjected isolated extensor digitorum longus (EDL) muscles from wild type mice to an ex vivo exercise protocol and verified that functional CEUs can assemble also in the absence of blood supply and innervation. Then, we evaluated whether parameters that are influenced by exercise, such as temperature and pH, may influence the assembly of CEUs. Results collected indicate that higher temperature (36 °C vs. 25 °C) and lower pH (7.2 vs. 7.4) increase the percentage of fibers containing SR stacks, the n. of SR stacks/area, and the elongation of TTs at the I band. Functionally, assembly of CEUs at higher temperature (36 °C) or at lower pH (7.2) correlates with increased fatigue resistance of EDL muscles in the presence of extracellular Ca2+. Taken together, these results indicate that CEUs can assemble in isolated EDL muscles and that temperature and pH are two of the possible regulators of CEU formation. Full article
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21 pages, 3500 KiB  
Article
Genetic Manipulation of CB1 Cannabinoid Receptors Reveals a Role in Maintaining Proper Skeletal Muscle Morphology and Function in Mice
by Zoltán Singlár, Nyamkhuu Ganbat, Péter Szentesi, Nomin Osgonsandag, László Szabó, Andrea Telek, János Fodor, Beatrix Dienes, Mónika Gönczi, László Csernoch and Mónika Sztretye
Int. J. Mol. Sci. 2022, 23(24), 15653; https://doi.org/10.3390/ijms232415653 - 09 Dec 2022
Cited by 6 | Viewed by 1776
Abstract
The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed [...] Read more.
The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed in human and murine skeletal muscle mainly in the cell membrane, but a subpopulation is present also in the mitochondria. However, very little is known about the latter population. To date, the connection between the function of CB1Rs and the regulation of intracellular Ca2+ signaling has not been investigated yet. Tamoxifen-inducible skeletal muscle-specific conditional CB1 knock-down (skmCB1-KD, hereafter referred to as Cre+/−) mice were used in this study for functional and morphological analysis. After confirming CB1R down-regulation on the mRNA and protein level, we performed in vitro muscle force measurements and found that peak twitch, tetanus, and fatigue were decreased significantly in Cre+/− mice. Resting intracellular calcium concentration, voltage dependence of the calcium transients as well as the activity dependent mitochondrial calcium uptake were essentially unaltered by Cnr1 gene manipulation. Nevertheless, we found striking differences in the ultrastructural architecture of the mitochondrial network of muscle tissue from the Cre+/− mice. Our results suggest a role of CB1Rs in maintaining physiological muscle function and morphology. Targeting ECS could be a potential tool in certain diseases, including muscular dystrophies where increased endocannabinoid levels have already been described. Full article
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Review

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25 pages, 1101 KiB  
Review
Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review
by Roland Takács, Patrik Kovács, Rana Abdelsattar Ebeid, János Almássy, János Fodor, László Ducza, Richard Barrett-Jolley, Rebecca Lewis and Csaba Matta
Int. J. Mol. Sci. 2023, 24(7), 6796; https://doi.org/10.3390/ijms24076796 - 05 Apr 2023
Cited by 1 | Viewed by 2412
Abstract
Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has [...] Read more.
Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms. Ion channels and the bioelectric signals they generate control the proliferation, differentiation, and migration of musculoskeletal progenitor cells. Calcium- and voltage-activated potassium (KCa) channels are key players in cell physiology in cells of the musculoskeletal system. This review article focused on the big conductance (BK) KCa channels. The regulatory function of BK channels requires interactions with diverse sets of proteins that have different functions in tissue-resident stem cells. In this narrative review article, we discuss the main ion channels of musculoskeletal stem cells, with a focus on calcium-dependent potassium channels, especially on the large conductance BK channel. We review their expression and function in progenitor cell proliferation, differentiation, and migration and highlight gaps in current knowledge on their involvement in musculoskeletal diseases. Full article
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