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Cells
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Skeletal Muscle Ion Channels in Health and Diseases
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Skeletal Muscle Ion Channels in Health and Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 18037

Special Issue Editor

Prof. Annamaria De Luca

E-Mail Website
Guest Editor
Department of Pharmacy – Drug Sciences, Università degli Studi di Bari, Bari, Italy
Interests: muscle disorders; translational pharmacology; physiology; electrophysiology; muscular dystrophies; ion channels; inherited and acquired channelopathies; excitation-contraction coupling; mechano-transduction; inflammation; dysmetabolism; standardization of animal models; drug discovery

Special Issue Information

Dear Colleagues,

Ion channels are membrane proteins that selectively regulate ion fluxes across the membranes of cells and cellular organelles, their gating mechanism depending on changes in membrane voltage, ligand binding or physical and chemical stimuli. In the skeletal muscle, the presence of distinct ion channel isoforms and their age-dependent expression are fundamental for skeletal muscle excitability and force development, but also allow the fine regulation of other cellular functions, such as muscle cell differentiation and regeneration and mechanical-metabolic adaptation, in dependence of specific muscle phenotypes and physiological stimuli. The wide spectrum of pathophysiological conditions associated with modification of ion channel activity, either as the primary cause, such as in myotonia, periodic paralysis or tubular aggregate myopathy, or as a secondary adaptive mechanism such as in some forms of muscular dystrophy, further support the importance of ion channels for skeletal muscle function. Besides being biomarkers of often rare diseases, ion channels are also appealing therapeutic targets for skeletal muscle disorders; sodium channel blockers have been long used for the treatment of non-dystrophic myotonias, and emerging evidence suggests the relevance of skeletal muscle purinergic receptors and TRP channels in drug discovery. In this context, gene-targeted animal models, patients’ derived muscular cells and skeletal muscle organoids, pharmacogenetics and drug-repurposing are all emerging approaches to advance the understanding of the roles of ion channels in skeletal muscle physiology and diseases and the development of precision medicines. This special issue will collect research papers and reviews addressing advancements in the field.

Prof. Annamaria De Luca
Guest Editor

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Keywords

  • skeletal muscle
  • ion channels
  • physiology
  • biophysics
  • channelopathies
  • muscle disorders
  • channel modulators
  • drugs
  • animal models
  • cell models

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Published Papers (4 papers)

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Research

Jump to: Review

17 pages, 4435 KiB  
Article
Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome
by Rosa Scala, Fatima Maqoud, Nicola Zizzo, Giuseppe Passantino, Antonietta Mele, Giulia Maria Camerino, Conor McClenaghan, Theresa M. Harter, Colin G. Nichols and Domenico Tricarico
Cells 2021, 10(7), 1791; https://doi.org/10.3390/cells10071791 - 15 Jul 2021
Cited by 12 | Viewed by 2963
Abstract
(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K+ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but [...] Read more.
(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K+ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2wt/AV) and homozygous SUR2[A478V] (SUR2AV/AV) CS mice. (3) Results: In SUR2wt/AV and SUR2AV/AV mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2wt/AV, dramatically so in SUR2AV/AV mice; IC50 for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10−5 M in SUR2wt/AV and 8.6 ± 0.4 × 10−6 M in WT mice and was not measurable in SUR2AV/AV. A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2AV/AV mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] “knock-in” mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2AV/AV, with atrophy and non-inflammatory edema in different skeletal muscle phenotypes. Full article
(This article belongs to the Special Issue Skeletal Muscle Ion Channels in Health and Diseases)
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20 pages, 26485 KiB  
Article
Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients
by Oscar Brenes, Raffaella Barbieri, Melissa Vásquez, Rebeca Vindas-Smith, Jeffrey Roig, Adarli Romero, Gerardo del Valle, Luis Bermúdez-Guzmán, Sara Bertelli, Michael Pusch and Fernando Morales
Cells 2021, 10(2), 374; https://doi.org/10.3390/cells10020374 - 11 Feb 2021
Cited by 3 | Viewed by 3978
Abstract
Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen’s disease. One novel mutation (p.W322*) in CLCN1 and one undescribed [...] Read more.
Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen’s disease. One novel mutation (p.W322*) in CLCN1 and one undescribed mutation (p.R1463H) in SCN4A are segregating in this family. The CLCN1-p.W322* was also found in an unrelated family, in compound heterozygosity with the known CLCN1-p.G355R mutation. One reported mutation, SCN4A-p.T1313M, was found in a third family. Both CLCN1 mutations exhibited loss-of-function: CLCN1-p.W322* probably leads to a non-viable truncated protein; for CLCN1-p.G355R, we predict structural damage, triggering important steric clashes. The SCN4A-p.R1463H produced a positive shift in the steady-state inactivation increasing window currents and a faster recovery from inactivation. These gain-of-function effects are probably due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD) IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that CLCN1-p.W322* and SCN4A-p.R1463H mutations can act alone or in combination as inducers of myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to provide accurate genetic counseling and management of patients. Full article
(This article belongs to the Special Issue Skeletal Muscle Ion Channels in Health and Diseases)
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Review

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16 pages, 720 KiB  
Review
Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle
by Nancy Tarantino, Ileana Canfora, Giulia Maria Camerino and Sabata Pierno
Cells 2022, 11(3), 415; https://doi.org/10.3390/cells11030415 - 25 Jan 2022
Cited by 9 | Viewed by 5569
Abstract
Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function [...] Read more.
Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue. Full article
(This article belongs to the Special Issue Skeletal Muscle Ion Channels in Health and Diseases)
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23 pages, 2223 KiB  
Review
Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond
by Elena Conte, Paola Imbrici, Paola Mantuano, Maria Antonietta Coppola, Giulia Maria Camerino, Annamaria De Luca and Antonella Liantonio
Cells 2021, 10(10), 2722; https://doi.org/10.3390/cells10102722 - 12 Oct 2021
Cited by 9 | Viewed by 4390
Abstract
Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated [...] Read more.
Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential. Full article
(This article belongs to the Special Issue Skeletal Muscle Ion Channels in Health and Diseases)
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