Impaired calcium release during fatigue

Allen, David G.; Lamb, Graham D.; Westerblad, Håkan

doi:10.1152/japplphysiol.00908.2007

Cited by 187 publications

(156 citation statements)

References 131 publications

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“…This decline of [ATP] significantly retards its capacity as the major cytoplasmic buffer of Mg 2+ , causing a parallel rise in free [Mg 2+ ] cyto . Indeed, increases in free [Mg 2+ ] cyto to levels in the order of 1.5-3 mM are reached during metabolic fatigue (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Choi

Koenig

Launikonis

2017

Proc. Natl. Acad. Sci. U.S.A.

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Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca 2+ transients elicited by MH triggers are unknown. Here, we show that Ca 2+ release in the absence of Mg 2+ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg 2+ ] (free [Mg 2+ ] cyto ) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca 2+ waves in the presence of resting levels of free [Mg 2+ ] cyto (1 mM). However, an increase of free [Mg 2+ ] cyto to 1.5 mM could increase the period between Ca 2+ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg 2+ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg 2+ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg 2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode. malignant hyperthermia | dantrolene | ryanodine receptor | magnesium | skeletal muscle fiber R yanodine receptors (RyRs) are essential regulators of cytoplasmic Ca 2+ in muscle, heart, and brain (1-3). Congenital or acquired mishandling of Ca 2+ by RyRs is associated with organ dysfunction, myopathy, and the increased risk of sudden death (1, 4-7). Consequently, the search for drugs to modulate RyR function is an area of intense research (8-10). An example of a successful drug controlling the Ca 2+ mishandling of the RyR is the muscle relaxant dantrolene (11). It is primarily used to treat malignant hyperthermia (MH), a life-threatening condition in which genetically predisposed individuals adversely react to the exposure of volatile anesthetics (5, 12). Since its approval, the drug has cut the mortality rate associated with MH from more than 80% to below 2% (11). Despite this success, the exact mechanism of how dantrolene antagonizes MH episodes and depresses overactive Ca 2+ release during MH episodes remains unknown.Susceptibility to MH most commonly arises from mutations in the RyR1 gene, the Ca 2+ release channel of skeletal muscle. Mg 2+ is present in the muscle at ∼1 mM and exerts an inhibitory action over the RyR1, which needs to be overcome for normal voltagecontrolled Ca 2+ release (13-16). RyR1 variants have a lowered affinity for Mg 2+ (13,17), making them more prone to opening and resulting in increased sensitivity to RyR agonist. The ensuing abnormal Ca 2+ release in RyR variants (18-24) during an MH event leads to excessive heat production as the muscle attempts to clear the...

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Section: Discussionmentioning

confidence: 99%

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Choi

Koenig

Launikonis

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Tel./Fax: +351 217805219; E-mail: mamedemg@mail.telepac.pt. of adenosine receptors, sparing muscle fiber glycogen reserve [1]; secondly, a positive direct effect on calcium release from the sarcoplasmic reticulum by ryanodine receptors activation, a phenomenon readily observed in situ muscle preparation but with a non-physiological level of caffeine [2]; thirdly, increasing excitatory neurotransmitter activity as a consequence of adenosine receptor antagonism [3].…”

Section: Musclementioning

confidence: 99%

Electrophysiological Studies in Healthy Subjects Involving Caffeine

Carvalho

Marcelino

2010

JAD

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Abstract. We review the electrophysiological studies concerning the effects of caffeine on muscle, lower and upper motor neuron excitability and cognition. Several different methods have been used, such as electromyography, recruitment analysis, H-reflex, transcranial magnetic stimulation (TMS), electroencephalography and event-related potentials. The positive effect of caffeine on vigilance, attention, speed of reaction, information processing and arousal is supported by a number of electrophysiological studies. The evidence in favor of an increased muscle fiber resistance is not definitive, but higher or lower motor neuron excitability can occur as a consequence of a greater excitation of the descending input from the brainstem and upper motor neurons. TMS can address the influence of caffeine on the upper motor neuron. Previous studies showed that cortico-motor threshold and intracortical excitatory and inhibitory pathways are not influenced by caffeine. Nonetheless, our results indicate that cortical silent period (CSP) is reduced in resting muscles after caffeine consumption, when stimulating the motor cortex with intensities slightly above threshold. We present new data demonstrating that this effect is also observed in fatigued muscle. We conclude that CSP can be considered a surrogate marker of the effect of caffeine in the brain, in particular of its central ergogenic effect.

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“…The causes of muscular weakness are probably complex, but it seems that a significant factor is the level of phosphocreatine, which falls significantly once the individual critical limit has been exceeded, while the concentration of inorganic phosphate rises [14]. On entering the sarcoplasmic reticulum inorganic phosphate can -by means of the subsequent release of calcium cations -significantly influence subsequent muscle contraction [1]. Creatine is solely under aerobic conditions re-phosphorylated into high-energy phosphocreatine [8], accompanied by a reduction in inorganic phosphate.…”

Section: Introductionmentioning

confidence: 99%

The effect of inhaling concentrated oxygen on performance during repeated anaerobic exercise

Suchý¹,

Heller²,

Bunc³

2010

Biol Sport

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ABSTRACT:The objective of the pilot study was to test the effect of inhaling 99.5% oxygen on recovery. The source of concentrated oxygen was O-PUR (Oxyfit). Research subjects completed two thirty-second Wingate tests at an interval of ten minutes, and in the interval between the tests the subjects inhaled either oxygen or a placebo in random order. This procedure was then repeated. The pilot study revealed a significantly (p<0.03) smaller performance drop in the second Wingate test following the inhalation of 99.5% oxygen when compared with the placebo. The results of the study indicate that inhaling concentrated oxygen may have a positive effect on short-term recovery processes. KEY WORDS: concentrated oxygen, anaerobic capacity, Wingate test, recovery speedconditions it is possible to increase the intensity of exertion during hyperoxic breathing. Symptoms of hyperventilation and the associated respiratory alkalosis (tachycardia, sweating, pins and needles, muscle spasms or shortened reflex times) have not been observed during the application of an increased concentration of oxygen. The inhalation of oxygen in higher concentrations leads to an increase in the arterial partial pressure of oxygen [16].

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Impaired calcium release during fatigue

Abstract: Allen DG, Lamb GD, Westerblad H. Impaired calcium release during fatigue.

Cited by 187 publications

References 131 publications

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Electrophysiological Studies in Healthy Subjects Involving Caffeine

The effect of inhaling concentrated oxygen on performance during repeated anaerobic exercise

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Impaired calcium release during fatigue

Abstract: Allen DG, Lamb GD, Westerblad H. Impaired calcium release during fatigue.

Cited by 187 publications

References 131 publications

Dantrolene requires Mg 2+ to arrest malignant hyperthermia

Dantrolene requires Mg 2+ to arrest malignant hyperthermia

Electrophysiological Studies in Healthy Subjects Involving Caffeine

The effect of inhaling concentrated oxygen on performance during repeated anaerobic exercise

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Product

Resources

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Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia