Regulation of ClC-1 and KATP channels in action potential–firing fast-twitch muscle fibers

Pedersen, Thomas Klit; Paoli, Frank Vincenzo de; Flatman, J. A.; Nielsen, Ole Bækgaard

doi:10.1085/jgp.200910290111709c

Cited by 42 publications

(82 citation statements)

References 61 publications

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“…Being an ion channel, it also links the excitability of the sarcolemma to the metabolic state of the fiber. There is now clear evidence that activation of K ATP channels during repetitive stimulation coincides with the activation of Cl 2 channels as discussed above (Pedersen et al, 2009a), and that the channel is crucial in preventing fiber damage and severe muscle dysfunction during exercise and fatigue by decreasing muscle cell excitability (Cifelli et al, 2008;Cifelli et al, 2007;Kane et al, 2004;Stoller et al, 2009;Thabet et al, 2005).…”

Section: Regulation and Impact Of The K Atp Channelmentioning

confidence: 82%

“…In the resting state, Cl 2 permeability largely exceeds that of K + (Palade and Barchi, 1977;Pedersen et al, 2009a;Pedersen et al, 2005;Pedersen et al, 2009b) and plays a major role in the maintenance of resting membrane potential (E m ). For example, when [K + ] e increases, the resulting membrane depolarization is slower and smaller when Cl 2 is present in the muscle bathing solution than in its complete absence (Dulhunty, 1978 (Pedersen et al, 2005).…”

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

“…If the observed modulation has any physiological significance, one would expect that there would be some regulation of the Cl 2 permeability by controlling the ClC-1 activity. In fact, during repeated contractions in rat extensor digitorum longus (EDL) fibers, Cl 2 permeability initially decreases by 50% within 1 minute (Pedersen et al, 2009a). As the stimulation is prolonged, Cl 2 permeability remains constant for 3 minutes and then suddenly increases by threefold above the pre-stimulation level, corresponding with opening of a very large number of ClC-1 channels.…”

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

“…As the stimulation is prolonged, Cl 2 permeability remains constant for 3 minutes and then suddenly increases by threefold above the pre-stimulation level, corresponding with opening of a very large number of ClC-1 channels. Associated with the increase in Cl 2 permeability is a decrease in membrane excitability (Pedersen et al, 2009a). Thus, ClC-1 is controlled during muscle activity.…”

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

“…This finding came from studies in which the K ATP channel activity is abolished by either exposing normal muscles to channel blockers or by using muscles from Kcnj11-null mice [mice in which the Kcnj11 (Kir6.2) gene that encodes the channel pore protein has been deleted]. Normally, resting E m depolarizes ] i during contraction is involved in the closing of ClC1, possibly through the activation of protein kinase C (Pedersen et al, 2009a;Pedersen et al, 2009b). The subsequent decrease in Cl 2 permeability improves action potential amplitude, thus counteracting the K + -depressing effect.…”

Section: Regulation and Impact Of The K Atp Channelmentioning

confidence: 99%

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Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

MacIntosh¹,

Holash²,

Renaud³

2012

Journal of Cell Science

100

119

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Summary ATP provides the energy in our muscles to generate force, through its use by myosin ATPases, and helps to terminate contraction by pumping Ca 2+ back into the sarcoplasmic reticulum, achieved by Ca 2+ ATPase. The capacity to use ATP through these mechanisms is sufficiently high enough so that muscles could quickly deplete ATP. However, this potentially catastrophic depletion is avoided. It has been proposed that ATP is preserved not only by the control of metabolic pathways providing ATP but also by the regulation of the processes that use ATP. Considering that contraction (i.e. myosin ATPase activity) is triggered by release of Ca 2+ , the use of ATP can be attenuated by decreasing Ca 2+ release within each cell. A lower level of Ca 2+ release can be accomplished by control of membrane potential and by direct regulation of the ryanodine receptor (RyR, the Ca 2+ release channel in the terminal cisternae). These highly redundant control mechanisms provide an effective means by which ATP can be preserved at the cellular level, avoiding metabolic catastrophe. This Commentary will review some of the known mechanisms by which this regulation of Ca 2+ release and contractile response is achieved, demonstrating that skeletal muscle fatigue is a consequence of attenuation of contractile activation; a process that allows avoidance of metabolic catastrophe.Key words: Endurance, Membrane excitability, Skeletal muscle contraction Introduction Typically, when exercise scientists think of control of skeletal muscle contraction, they consider motor unit recruitment and rate coding, the primary means by which the brain regulates the magnitude of muscle contraction. However, the magnitude of skeletal muscle contraction can also be regulated at the cellular level. This level of control is necessary to avoid cellular metabolic catastrophe, i.e. the situation in which ATP depletion reaches a level that is damaging to the fiber.ATP is the common final source for energy in the cell, and its concentration [along with the concentrations of ADP and inorganic phosphate (Pi)] affects the magnitude of energy that is made available from its hydrolysis. At rest, skeletal muscle has a low metabolic rate, not unlike many other passive tissues, and the intracellular concentration of ATP is in the 5-7 mM range (Hochachka and Matheson, 1992). However, during muscle activity, there are three major ATPases that require ATP for their function (Box 1); during exercise, skeletal muscle can increase its rate of ATP use by more than 100 times (Hochachka and McClelland, 1997), a rate that is much faster than can be replenished by aerobic metabolism. This latter point is clear from the fact that the muscle power output can greatly exceed the level that can be supported by aerobic metabolism (MacIntosh et al., 2000). To accommodate this additional energy requirement, ATP is provided by non-aerobic means (through phosphocreatine hydrolysis and glycolysis resulting in lactate formation), but this alternative source of ATP has limited capacity (Monod ...

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Section: Regulation and Impact Of The K Atp Channelmentioning

confidence: 82%

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

Section: Regulation and Impact Of The K Atp Channelmentioning

confidence: 99%

See 3 more Smart Citations

Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

MacIntosh¹,

Holash²,

Renaud³

2012

Journal of Cell Science

100

119

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Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Novak

Norman

Mitchell

et al. 2015

Annals of Neurology

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Objective Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warm-up phenomenon. Our goal was to identify the mechanism underlying warm up and to use this information to guide development of novel therapy. Methods To determine the mechanism underlying warm-up, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warm-up in a mouse model of myotonia congenita. Results Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warm-up. These data suggested enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are FDA-approved for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine’s hypoexcitability side effects. Interpretation We conclude ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

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Inhibiting persistent inward sodium currents prevents myotonia

Hawash

Voss

Rich

2017

Annals of Neurology

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ObjectivePatients with myotonia congenita have muscle hyperexcitability due to loss‐of‐function mutations in the ClC‐1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC‐1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC‐1 current.Methods In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.ResultsIntracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin‐sensitive and voltage‐dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.InterpretationThis work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. Ann Neurol 2017;82:385–395

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Regulation of ClC-1 and KATP channels in action potential–firing fast-twitch muscle fibers

Cited by 42 publications

References 61 publications

Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Inhibiting persistent inward sodium currents prevents myotonia

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