Increased Excitability of Acidified Skeletal Muscle

Pedersen, Thomas Klit; Paoli, Frank de; Nielsen, Ole Bækgaard

doi:10.1085/jgp.200409173

Cited by 127 publications

(188 citation statements)

References 38 publications

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“…31 In addition, higher metabolism in the periphery during night sweats could lead to a build-up of lactic acid in the muscles, which leads to an increased excitability of nervemuscle plates and to more frequent PLMs. 32 Although PLMs were significantly associated with vasomotor symptoms in the present study, no such association was found in women with PLM arousals. It is likely that the current study simply did not contain enough women with PLM arousals to reveal significant associations with menopause and/ or vasomotor symptoms (indicating a type II error).…”

Section: Discussioncontrasting

confidence: 75%

Periodic Limb Movements Are Associated with Vasomotor Symptoms

Wesström

Ulfberg²,

Sundström‐Poromaa

et al. 2014

Journal of Clinical Sleep Medicine

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diagnosis of periodic limb movement disorder (PLMD) is established when the affected individual also has insomnia and/or excessive daytime drowsiness. By subjective reports, the prevalence of PLMD has been estimated to be 3.9% in the general population. Restless legs syndrome (RLS) is a common sensory-motor disorder that produces uncomfortable sensations and a constant urge to move the lower limbs, and has a typical diurnal pattern with a peak of symptoms during rest periods in the evening and at night. RLS has also been reported to be associated with cardiovascular disease (CVD). 8 In contrast to PLMs, the diagnosis of RLS is based on the patient's subjective symptoms. PLMs are related to RLS, and the majority of patients with RLS display PLMs during sleep. 9 Prior studies have discussed the S C I E N T I F I C I N V E S T I G A T I O N SP eriodic limb movements (PLMs) during sleep were fi rst described in 1953 as "nocturnal myoclonus," and were at that time thought to have similarities to nocturnal epilepsy. 1The pathophysiological mechanisms of PLMs are unclear, but abnormal hyperexcitability (or diminished inhibition) in the lumbosacral and cervical segments of the spinal cord have been hypothesized to be possible causes.2 PLMs are characterized by involuntary movements of the lower extremities, specifi cally the toes, ankle, knees, and hips, typically lasting between 0.5 and 10 seconds. The patient is usually unaware of the limb movements or the frequent sleep disruptions, and PLMs are often an incidental fi nding at polysomnography (PSG).3 PLMs may cause microarousals, leaving the affected patient fatigued the following day. Previously, it was assumed that PLMs were the cause of these arousals, but more recent studies have revealed that PLMs and arousals are associated in a more complex and non-unidirectional manner. Arousals can occur before, during, and after leg movements, indicating that the phenomenon is associated with an underlying arousal disorder. 4 The exact prevalence of PLMs is unknown. They appear to be rare in children, to progress with advancing age, and to be more common in females than in males. 5,6 In studies where PLMs have been objectively documented (PLM episodes/h of sleep > 5), the prevalence was 5% to 6% in younger adults, and 25% to 58% among elderly people. BRIEF SUMMARYCurrent Knowledge/Study Rationale: Sleep disturbances affect a substantial fraction of women during the menopausal transition, and female sex hormones are possibly involved in the origin of PLMs. It is currently unknown whether PLMs are associated with the menopausal transition and/or concomitant vasomotor symptoms. Study Impact: This study shows an association between symptoms related to declining levels of estrogen, i.e. vasomotor symptoms, and PLMs. Future studies should address the possibility of using hormone replacement therapy in postmenopausal women with PLMD.

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Section: Discussioncontrasting

confidence: 75%

Periodic Limb Movements Are Associated with Vasomotor Symptoms

Wesström

Ulfberg²,

Sundström‐Poromaa

et al. 2014

Journal of Clinical Sleep Medicine

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“…In our experiments, with 5 mM ATP, the normal level in resting or moderately exercising muscle, a reduction of pH i of this magnitude markedly shifted the voltage dependence of ClC-1 common gating to more positive potentials, inhibiting ClC-1 activity by reducing its open probability across the physiological voltage range. Inhibition of ClC-1 by low intracellular pH in the presence of ATP is therefore likely to be the molecular mechanism underlying the reduction in sarcolemmal chloride conductance with acidosis that leads to increased membrane excitability (10,11).…”

Section: Discussionmentioning

confidence: 99%

“…Acidification has been shown to result in recovery of muscle excitability and force when these have decreased due to elevated extracellular [K ϩ ] (9). More recent studies have shown that increased excitability at low intracellular pH (pH i ) is due to reduced chloride conductance of the muscle membrane (10,11). Low pH has long been known to reduce G Cl in muscle membranes (12,13), but previous studies of the pH sensitivity of recombinantly expressed ClC-1 have failed to reconcile the reduction of G Cl of the membrane with a molecular mechanism acting directly on ClC-1.…”

mentioning

confidence: 99%

Inhibition of Skeletal Muscle ClC-1 Chloride Channels by Low Intracellular pH and ATP

Bennetts

Parker²,

Cromer

2007

Journal of Biological Chemistry

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Skeletal muscle acidosis during exercise has long been thought to be a cause of fatigue, but recent studies have shown that acidosis maintains muscle excitability and opposes fatigue by decreasing the sarcolemmal chloride conductance. ClC-1 is the primary sarcolemmal chloride channel and has a clear role in controlling muscle excitability, but recombinant ClC-1 has been reported to be activated by acidosis. Following our recent finding that intracellular ATP inhibits ClC-1, we investigated here the interaction between pH and ATP regulation of ClC-1. We found that, in the absence of ATP, intracellular acidosis from pH 7.2 to 6.2 inhibited ClC-1 slightly by shifting the voltage dependence of common gating to more positive potentials, similar to the effect of ATP. Importantly, the effects of ATP and acidosis were cooperative, such that ATP greatly potentiated the effect of acidosis. Adenosine had a similar effect to ATP at pH 7.2, but acidosis did not potentiate this effect, indicating that the phosphates of ATP are important for this cooperativity, possibly due to electrostatic interactions with protonatable residues of ClC-1. A protonatable residue identified by molecular modeling, His-847, was found to be critical for both pH and ATP modulation and may be involved in such electrostatic interactions. These findings are now consistent with, and provide a molecular explanation for, acidosis opposing fatigue by decreasing the chloride conductance of skeletal muscle via inhibition of ClC-1. The modulation of ClC-1 by ATP is a key component of this molecular mechanism.

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“…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). Reducing Cl 2 permeability by 50% allows for a recovery of membrane excitability; the number of fibers generating action potentials increases to 95% and action potential peak reaches +10 mV.…”

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

“…Lowering Cl 2 permeability by closing Cl 2 channels lowers Cl 2 influx, thus diminishing its ability to counteract the Na + depolarization and allowing for greater action potential amplitude. Associated with the increase in membrane excitability is an increase in force production (Pedersen et al, 2005 Regulation of excitation-contraction coupling in fatigue 2109 channels are closed improves membrane excitability and force generation.…”

Section: Regulation and Impact Of The Clc-1mentioning

confidence: 99%

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

MacIntosh¹,

Holash²,

Renaud³

2012

Journal of Cell Science

101

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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Increased Excitability of Acidified Skeletal Muscle

Cited by 127 publications

References 38 publications

Periodic Limb Movements Are Associated with Vasomotor Symptoms

Periodic Limb Movements Are Associated with Vasomotor Symptoms

Inhibition of Skeletal Muscle ClC-1 Chloride Channels by Low Intracellular pH and ATP

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

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