ryanodine and Muscular-Diseases

Topics: Action Potentials; Animals; Caffeine; Calcium; Calcium Channels; CHO Cells; Cricetinae; Dihydropyridines; Genes; Humans; Malignant Hyperthermia; Mammals; Mice; Mice, Mutant Strains; Muscle Contraction; Muscle Proteins; Muscular Diseases; Myocardial Contraction; Organ Specificity; Protein Engineering; Receptors, Nicotinic; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Transduction

Statins, inhibitors of HMG-CoA reductase, are mainstay treatment for hypercholesterolaemia. However, muscle pain and weakness prevent many patients from benefiting from their cardioprotective effects. We previously demonstrated that simvastatin activates skeletal ryanodine receptors (RyR1), an effect that could be important in initiating myopathy. Using a range of structurally diverse statin analogues, we examined structural features associated with RyR1 activation, aiming to identify statins lacking this property.. Compounds were screened for RyR1 activity utilising [. All UK-prescribed statins activated RyR1 at nanomolar concentrations. Cerivastatin, withdrawn from the market due to life-threatening muscle-related side effects, was more effective than currently-prescribed statins and possessed the unique ability to open RyR1 channels independently of cytosolic Ca. That cerivastatin activates RyR1 most strongly supports the hypothesis that RyR1 activation is implicated in statin-induced myopathy. Demonstrating that statin regulation of RyR1 and HMG-CoA reductase are separable effects will allow the role of RyR1 in statin-induced myopathy to be further elucidated by the tool compounds we have identified, allowing development of effective cardioprotective statins with improved patient tolerance.

Topics: Acyl Coenzyme A; Animals; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Muscle, Skeletal; Muscular Diseases; Rabbits; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sheep; Simvastatin

The skeletal muscle ryanodine receptor plays a crucial role in excitation-contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca(2+) release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

Topics: Adult; Arginine; Caffeine; Calcium; Calcium Channels; Calcium Channels, L-Type; Cell Line, Transformed; DNA Mutational Analysis; Electron Transport Complex IV; Family Health; Female; Humans; Lysine; Male; Membrane Potentials; Muscle, Skeletal; Muscular Diseases; Mutation; NAV1.4 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Phosphodiesterase Inhibitors; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sodium Channels; Transfection; Tritium

Malignant hyperthermia may be a human stress syndrome, of which heat stroke is one manifestation. Two men in military service who had episodes of exertional heat stroke, and their immediate family members, were tested for susceptibility to malignant hyperthermia by in-vitro contracture tests on skeletal muscle samples. Muscle from both patients had a normal response to caffeine but an abnormal response to halothane. Muscle from the father of one patient had an abnormal response to halothane, and that from the father of the second patient had an abnormal response to ryanodine. The results indicate that clinical heat stroke may be associated with an underlying inherited abnormality of skeletal muscle that is similar, but not identical, to that of malignant hyperthermia.

Topics: Adult; Biopsy; Caffeine; Disease Susceptibility; Family Health; Female; Halothane; Heat Exhaustion; Humans; In Vitro Techniques; Male; Malignant Hyperthermia; Military Personnel; Muscle Contraction; Muscles; Muscular Diseases; Physical Exertion; Ryanodine

The different membrane systems and proteins involved in the control of intracellular calcium movements in the skeletal muscle cell are described. These include the sarcoplasmic reticulum, that Ca(++)-ATPase sarcoplasmic reticular calcium pump, transverse tubules, calcium channels, and the ryanodine receptor protein. The significance of these systems is shown clearly in the myopathies, where the main errors involved do not concern the contractile system, but the command and control mechanisms.

Topics: Calcium; Calcium Channels; Calcium-Transporting ATPases; Dihydropyridines; Humans; Muscle Contraction; Muscles; Muscular Diseases; Myofibrils; Receptors, Cell Surface; Ryanodine; Sarcoplasmic Reticulum