Chloride Channels Take Center Stage in Acute Regulation of Excitability in Skeletal Muscle: Implications for Fatigue

Nielsen, Ole Bækgaard; Paoli, Frank Vincenzo de; Riisager, Anders; Pedersen, Thomas Klit

doi:10.1152/physiol.00006.2015

Cited by 25 publications

(25 citation statements)

References 109 publications

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“…The biophysical properties, structure, and role of the chloride channel (ClC-1) in muscle physiology have been extensively investigated for more than 20 years (Aromataris and Rychkov, 2006;Tang and Chen, 2011;Imbrici et al, 2015;Pedersen et al, 2016;Baekgaard Nielsen et al, 2017;Jentsch and Pusch, 2018;Park and MacKinnon, 2018;Wang et al, 2019). ClC-1, encoded by the Clcn1 gene, is exclusively present in skeletal muscle (Steinmeyer et al, 1991;Pedersen et al, 2016) where it mediates the bulk of plasma membrane Cl conductance (gCl).…”

Section: Introductionmentioning

confidence: 99%

“…ClC-1, encoded by the Clcn1 gene, is exclusively present in skeletal muscle (Steinmeyer et al, 1991;Pedersen et al, 2016) where it mediates the bulk of plasma membrane Cl conductance (gCl). ClC-1 is important for muscle function as it stabilizes resting membrane potential and helps to repolarize the membrane after action potentials (Baekgaard Nielsen et al, 2017;Jentsch and Pusch, 2018;Phillips and Trivedi, 2018;Ravenscroft et al, 2018). Today, it is known that different types of Clcn1 mutations are responsible for dominant and recessive myotonia (Desaphy et al, 2013;Poroca et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Changes in Expression and Cellular Localization of Rat Skeletal Muscle ClC-1 Chloride Channel in Relation to Age, Myofiber Phenotype and PKC Modulation

Conte¹,

Fonzino²,

Cibelli³

et al. 2020

Front. Pharmacol.

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The ClC-1 chloride channel 1 is important for muscle function as it stabilizes resting membrane potential and helps to repolarize the membrane after action potentials. We investigated the contribution of ClC-1 to adaptation of skeletal muscles to needs induced by the different stages of life. We analyzed the ClC-1 gene and protein expression as well as mRNA levels of protein kinase C (PKC) alpha and theta involved in ClC-1 modulation, in soleus (SOL) and extensor digitorum longus (EDL) muscles of rats in all stage of life. The cellular localization of ClC-1 in relation to age was also investigated. Our data show that during muscle development ClC-1 expression differs according to phenotype. In fasttwitch EDL muscles ClC-1 expression increased 10-fold starting at 7 days up to 8 months of life. Conversely, in slow-twitch SOL muscles ClC-1 expression remained constant until 33 days of life and subsequently increased fivefold to reach the adult value. Aging induced a downregulation of gene and protein ClC-1 expression in both muscle types analyzed. The mRNA of PKC-theta revealed the same trend as ClC-1 except in old age, whereas the mRNA of PKC-alpha increased only after 2 months of age. Also, we found that the ClC-1 is localized in both membrane and cytoplasm, in fibers of 12-day-old rats, becoming perfectly localized on the membrane in 2-month-old rats. This study could represent a point of comparison helpful for the identification of accurate pharmacological strategies for all the pathological situations in which ClC-1 protein is altered.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Changes in Expression and Cellular Localization of Rat Skeletal Muscle ClC-1 Chloride Channel in Relation to Age, Myofiber Phenotype and PKC Modulation

Conte¹,

Fonzino²,

Cibelli³

et al. 2020

Front. Pharmacol.

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“…It also helps explain how the ischemic membrane-damaged SMFs of DMD patients can survive for decades (Morris et al submitted). Given appropriate refinements, SM-CD modeling should be helpful in connection with muscle fatigue, endurance, trauma, volume regulation, ischemia-reperfusion injury, ion channelopathies, hibernation, cold tolerance, sarcopenia and more (e.g., Donohue et al 2000; Lindinger et al 2011; dePaoli et al 2013; Yu et al 2013; Clausen 2015; Ammar et al 2015; Bækgaard Nielsen et al 2017; Boërio et al 2018; Hostrup and Bangsbo 2017; Hotfiel et al 2018; Cannon 2018; Copithorne and Rice 2019; Li et al 2020; Metzger et al 2020; Altamura et al 2020; Surkar et al 2020; Thoma et al 2020).…”

Section: Discussionmentioning

confidence: 99%

The Pump-Leak/Donnan ion homeostasis strategies of skeletal muscle fibers and neurons

Joós

Morris

2020

Preprint

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Skeletal muscle fibers (SMFs) and neurons are low and high duty-cycle excitable cells constituting exceptionally large and extraordinarily small fractions of vertebrate bodies. The immense ClC-1-based chloride-permeability (PCl) of SMFs has thwarted understanding of their Pump-Leak/Donnan (P-L/D) ion homeostasis. After formally defining P-L/D set-points and feedbacks, we therefore devise a simple yet demonstrably realistic model for SMFs. Hyper-stimulated, it approximates rodent fibers’ ouabain-sensitive ATP-consumption. Size-matched neuron-model/SMF-model comparisons reveal steady-states occupying two ends of an energetics/resilience P-L/D continuum. Excitable neurons’ costly vulnerable process is Pump-Leak dominated. Electrically-reluctant SMFs’ robust low-cost process is Donnan dominated: collaboratively, Donnan effectors and [big PCl] stabilize Vrest, while SMFs’ exquisitely small PNa minimizes ATP-consumption, thus maximizing resilience. “Classic” excitable cell homeostasis ([small PCl][big INaleak]), de rigueur for electrically-agile neurons, is untenable for vertebrates’ (including humans’) major tissue. Vertebrate bodies evolved thanks to syncytially-efficient SMFs using a Donnan dominated ([big PCl][small INaleak]) ion homeostatic strategy.

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“…Several lines of evidence suggest that regulation of skeletal muscle fatigue involves alteration of ClC-1 channel activation (62,(71)(72)(73)(74). During exercise, intensive firing of action potentials associated with active muscle contractions may result in extracellular accumulation of potassium (K + ) ions, which in turn would depolarize muscle membrane potential and thereby induce slow inactivation of voltage-gated Na + channels.…”

Section: Structure and Function Of The Clc-1 Channelmentioning

confidence: 99%

“…On the other hand, in fast-twitch muscle fibers during prolonged muscle activities, the intracellular ATP level appears to be notably lowered (74,80), which in turn reduces ATP inhibition of ClC-1 common-gating. This enhanced opening of the ClC-1 channel is expected to decrease muscle excitability and may serve to safeguard the cellular integrity of fast-twitch muscle fibers during metabolic stress (73).…”

Section: Structure and Function Of The Clc-1 Channelmentioning

confidence: 99%

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

Jeng¹,

You

et al. 2020

Front. Neurol.

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The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this Jeng et al.ClC-1 Proteostasis and Myotonia chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

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Chloride Channels Take Center Stage in Acute Regulation of Excitability in Skeletal Muscle: Implications for Fatigue

Cited by 25 publications

References 109 publications

Changes in Expression and Cellular Localization of Rat Skeletal Muscle ClC-1 Chloride Channel in Relation to Age, Myofiber Phenotype and PKC Modulation

Changes in Expression and Cellular Localization of Rat Skeletal Muscle ClC-1 Chloride Channel in Relation to Age, Myofiber Phenotype and PKC Modulation

The Pump-Leak/Donnan ion homeostasis strategies of skeletal muscle fibers and neurons

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

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