Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026837 (muscle rigidity)
 1,077 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhabomyolysis with myoglobinuria has been added relatively recently to the neurologic complications associated with the increased use of cocaine and the introduction of its alkaloid form (crack). This retrospective study reports our experience with 14 patients who presented with rhabdomyolysis after cocaine use in a municipal hospital over a 3-year period. Seven patients used "crack", 2 intravenous and 3 nasal insufflation. All patients but one had hyperthermia, 11 altered mental status, 8 tachycardia, and 4 muscle rigidity. Nine developed renal failure; 3 of these patients died. Two other patients died of cardiorespiratory arrest. Cocaine-related rhabdomyolysis has a high mortality. The observed association with hyperthermia and other central neurologic features resembles the neuroleptic malignant syndrome. Since chronic cocaine use may alter the availability of dopamine either through transmitter depletion or decrease in the number of dopamine receptors, a common pathogenetic mechanism is possible. However, other mechanisms, which are not mutually exclusive but rather frequently overlapping, may play an important role. These include agitation, hyperthermia, adrenergic overstimulation leading to vasoconstriction and ischemia or calcium release from the sarcoplasmic reticulum resulting in increased entry into the muscle cell leading to cell death; in addition, cocaine has direct toxic effect on the muscles.
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PMID:Rhabdomyolysis and hyperthermia after cocaine abuse: a variant of the neuroleptic malignant syndrome? 748 66

The regulation of contractile activity in mice bearing a null mutation of the M-isoform of creatine kinase gene, has been investigated in tissue extracts and Triton X-100-treated preparations of ventricular, soleus, and gastrocnemius muscles of control and transgenic mice. Skinned fiber experiments did not evidence any statistical difference in the maximal force or the calcium sensitivity of either muscle type. Rigor tension development at a low MgATP concentration was greatly influenced by phosphocreatine in control but not in transgenic mice as should be expected. In calcium-activated ventricular preparations, although the force developed by each cross-bridge was the same in control and transgenic animals, the rate constant of tension changes appeared to be markedly slowed in transgenic animals. As the ventricular isomyosin pattern was not altered, we suggested that, in transgenic animals, cross-bridge cycling was hindered by a local decrease in the MgATP to MgADP ratio, due to lack of a local MgATP regenerating system. Myokinase activity was not significantly changed while activities of pyruvate kinase or glyceraldehyde-3-phosphate dehydrogenase were found to be increased in transgenic animals. These results show that no fundamental remodelling occurs in myofibrils of transgenic animals but that important adaptations modify the bioenergetic pathways including glycolytic metabolism.
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PMID:Muscle creatine kinase-deficient mice. I. Alterations in myofibrillar function. 765 6

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In humans, MH is inherited in an autosomal dominant fashion; in swine, the principal model for MH, it is in a recessive fashion. Those with MH susceptibility usually are asymptomatic except in the presence of certain "triggering" anaesthetic agents such as isoflurane, enflurane and the muscle relaxant succinylcholine. Upon such exposure hypermetabolism, increased CO2 production, acidosis, muscle rigidity, rhabdomyolysis and hyperthermia occur. Untreated, death may result in 70% of patients. With prompt diagnosis and treatment with dantrolene sodium, the mortality is less than 10%. The overall incidence of MH is low (perhaps 1:50,000 anaesthetics), but it is more common in children. Children also display a paradoxical increase in jaw muscle tone to succinylcholine which often presages MH, but confusing clinically, may also be a normal response to succinylcholine. The pathophysiology of MH centres around a defect in calcium flux in skeletal muscle. A specific base pair change in the gene that codes for the ryanodine receptor calcium channel in muscle has been demonstrated in susceptible swine, but occurs rarely in humans. It is hoped that the understanding of the molecular genetics of MH will lead to a simpler diagnostic test than is currently available, and enhance our understanding of MH and its relation to other myopathies.
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PMID:An update on the malignant hyperthermia syndrome. 771 Feb 42

The beneficial effect of low pH during cardiac ischemia on reperfusion injury has often been attributed to its energy-saving effect due to inhibition of contraction. The role of low pH on Ca2+ accumulation and muscle tension was assessed in energy-depleted tissue by changing the pH of the medium from 7.4 to 6.2 at onset of rigor development during metabolic inhibition (MI), i.e., in the energy-depleted phase. Cytosolic free Ca2+ ([Ca2+]i) and intracellular H+ (pHi) were measured in rat trabeculae at 20 degrees C with fura 2 and 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein, respectively, and tension was recorded. The preparations were energy depleted by stimulation at 1 Hz in glucose-free Tyrode solution with 2 mM NaCN. Rigor developed within 20 min, indicating energy depletion. Resting [Ca2+]i was followed during 50 min (group I) or 100 min (group II) of rigor, and recovery was followed for 60 min in glucose-containing Tyrode solution at 0.2-Hz stimulation. Resting [Ca2+]i rose within 50 min (group I) but stabilized in the 50- to 100-min period (group II). All preparations from group I (n = 5) resumed contraction in the recovery period but in group II (n = 10) 70% failed to recover, and [Ca2+]i remained elevated compared with those that recovered. An extracellular pH of 6.2, resulting in similar pHi, from onset of rigor development (group III) led to only a modest rise in [Ca2+]i during the 100-min rigor period, and all preparations resumed contraction after approximately 3 min in normal medium. ATP was very low in all groups at the end of MI but was still significantly lower in group II than in groups I and III. A beneficial energy-sparing effect of low pH during the rigor phase can therefore not be excluded. We conclude that 1) the capacity of trabeculae to recover from MI depends on the time period and magnitude of the [Ca2+]i rise in the energy-depleted phase and 2) low pH in energy-depleted trabeculae protects against Ca overload, improving recovery after normalization of perfusion conditions.
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PMID:Exposure of energy-depleted rat trabeculae to low pH improves contractile recovery: role of calcium. 773 52

Previous studies in isolated limbs using crystalloid perfusion solutions have shown that control of the initial reperfusion reduces postischaemic complications. However, no experimental study has been undertaken to evaluate the concept of controlled limb reperfusion experimentally in an in vivo blood-perfused model and to assess the local as well as systemic effects of normal blood reperfusion and controlled limb reperfusion. Of 20 pigs undergoing preparation of the infrarenal aorta and iliac arteries, six were observed for 7.5 h and served as controls; 14 others underwent 6 h of complete infrarenal occlusion. Thereafter, embolectomy was simulated in eight pigs by removing the aortic clamp and establishing normal blood reperfusion at systemic pressure. In six other pigs, the composition of the reperfusate and the conditions of reperfusion were controlled during the first 30 min, followed by normal blood reperfusion. Some 6 h of infrarenal aortic occlusion leads to a severe decrease in high-energy phosphates and muscle temperature, together with a slight increase in creatine kinase and potassium in the systemic circulation. Normal blood reperfusion resulted in severe reperfusion injury: massive oedema developed, the tissue showed a marked decrease in oxygen consumption, glucose consumption, tissue ATP, total adenine nucleotides, muscle pH and total calcium in the femoral vein. Furthermore, a massive increase was seen in plasma creatine kinase concentration and potassium, together with the development of muscle rigidity. In sharp contrast, initial treatment of the ischaemic skeletal muscle by controlled limb reperfusion resulted in normal water content, oxygen consumption, glucose consumption, flow and muscle rigidity. Furthermore, controlled limb reperfusion resulted in higher total adenine nucleotides content, less tissue acidosis, markedly reduced creatine kinase release, and potassium release as compared with that of normal blood reperfusion. This study shows that 6 h of acute infrarenal aortic occlusion will result in severe reperfusion injury (postischaemic syndrome) if normal blood at systemic pressure is given in the initial reperfusion phase. In contrast, initial treatment of the ischaemic skeletal muscle by controlled limb reperfusion reduces the metabolic, functional and biochemical alterations.
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PMID:Reperfusion injury in skeletal muscle: controlled limb reperfusion reduces local and systemic complications after prolonged ischaemia. 785 92

1. Ventricular trabeculae from rat heart were chemically skinned with Triton X-100, which disrupts all cellular membranes including the sarcoplasmic reticulum. In the effective absence of Ca2+ (10(-9) M), trabeculae developed a maintained rigor contracture when ATP was withdrawn from the bathing solution. 2. The final level of tension obtained following withdrawal of ATP was dependent upon the pH of the bathing solution during development of rigor. Rigor tension at pH 5.5 was 10.1 +/- 0.9% (n = 8, mean +/- S.E.M.) of that at pH 7.0. Bathing the preparation in alkaline solution increased rigor force. At pH 8.0, rigor force increased to 218 +/- 6.7% (n = 4) of control responses developed at pH 7.0. The rate of development of rigor tension increased as the pH of the bathing solution was increased. Once established, rigor tension was unaffected by subsequent changes in pH. These effects of pH were fully reversible within the range 5.5-8.0. 3. The final level of rigor tension was slightly reduced when inorganic phosphate (P(i)) was included in the bathing solution prior to withdrawal of ATP. P(i) concentrations of 10, 20 and 30 mM reduced rigor tension to 87 +/- 2, 83 +/- 3 and 82 +/- 4% respectively. There was no significant effect of P(i) on the rate of development of rigor. The effect of P(i) at pH 6.0 was not significantly different from that observed at the control pH of 7.0. 4. These results suggest that the fall of intracellular pH and, to a lesser extent, the rise in [P(i)] that occurs during ischaemia will partially inhibit the development of a rigor contracture.
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PMID:Effects of pH and inorganic phosphate on rigor tension in chemically skinned rat ventricular trabeculae. 796 60

Malignant hyperthermia (MH) susceptibility remains the commonest cause of death owing to general anaesthesia. In humans, genetically predisposed to MH, anaesthesia can induce skeletal muscle rigidity, hypermetabolism and hyperthermia, which if not immediately reversed can lead to tissue injury and death. In swine, the corresponding condition leads to stress-induced deaths and devalued meat products. Aberrant behaviour in the calcium (Ca2+) release channel (the ryanodine receptor) of skeletal muscle sarcoplasmic reticulum has been implicated in the cause of both the porcine and human syndromes by biochemical, physiological and molecular genetic analysis. In swine, a single mutation in the ryanodine receptor gene (RYR1) can account for all cases of MH in all breeds, but a series of different RYR1 mutation are uncovered in human families with MH. In addition, the lack of linkage between MH and RYR1 in some families indicates a heterogeneous genetic basis for the human MH.
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PMID:The genetic basis of malignant hyperthermia. 797 21

Malignant hyperthermia (MH), an inherited neuromuscular disease triggered by halogenated inhalational anaesthetics and skeletal-muscle relaxants, appears to be due to an alteration of intracellular Ca2+ homoeostasis. MH occurs in 1 out of 20,000 anaesthetized adults and is characterized by hypermetabolism, skeletal-muscle rigidity and elevation in body temperature, which is frequently fatal [MacLennan and Phillips (1992) Science 256, 789-794]. The defect responsible for the disease may lie within the mechanism controlling the release of Ca2+ from sarcoplasmic reticulum via the ryanodine-receptor (RYR) Ca2+ channel; in fact a point mutation in the RYR has been associated with MH in some human families, as well as in the MH-susceptible pig. To date, however, no direct evidence has been obtained demonstrating that the point mutation is both necessary and sufficient to cause functional alterations in RYR-mediated Ca2+ release. In the present report we show that the presence of the Arg-to-Cys point mutation in the recombinant RYR expressed in COS-7 transfected cells causes abnormal cytosolic Ca2+ transients in response to 4-chloro-m-cresol, an agent capable of eliciting in vitro contracture of MH-susceptible muscles.
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PMID:Alteration of intracellular Ca2+ transients in COS-7 cells transfected with the cDNA encoding skeletal-muscle ryanodine receptor carrying a mutation associated with malignant hyperthermia. 805 91

Myocardial ischemia is characterized by a decrease in phosphocreatine (PCr) and Mg(2+)-ATP contents as well as an accumulation of myosin ATPase reaction products (inorganic phosphate [P(i)], protons, and Mg(2+)-ADP). The possibility that these metabolites play a role in rigor tension development was checked in rat ventricular Triton X-100-skinned fibers. Rigor tension was induced by stepwise decreasing [Mg(2+)-ATP] in the presence or in the absence of 12 mmol/L PCr. To mimic the diastolic ionic environment of the myofibrils, [free Ca2+] was set at 100 nmol/L (pCa 7); [free Mg2+], at 1 mmol/L; and ionic strength, at 160 mmol/L. In control conditions (pH 7.1, with no added P(i) or Mg(2+)-ADP), the pMg(2+)-ATP for half-maximal rigor tension (pMg(2+)-ATP50) was 5.07 +/- 0.03 in the presence of PCr. After withdrawal of PCr, the pMg2+)-ATP50 value was shifted toward higher Mg(2+)-ATP values (3.57 +/- 0.03). Addition of 20 mmol/L P(i) shifted the pMg(2+)-ATP50 to 3.71 +/- 0.04 (P < .05) in the absence of PCr and in the opposite direction to 4.98 +/- 0.02 (P < .01) in the presence of PCr. Acidic pH (6.6) strongly increased pMg(2+)-ATP50 in both the absence (3.90 +/- 0.03, P < .001) and presence (5.44 +/- 0.02, P < .001) of PCr. Conversely, Mg(2+)-ADP (250 mumol/L) decreased pMg(2+)-ATP50 to 3.26 +/- 0.06 (P < .001) in the absence of PCr; at pMg(2+)-ATP 4, no rigor tension was observed until PCr concentration was decreased to < 2 mmol/L. At acidic pH, maximal rigor tension was lower by 29% compared with control conditions, whereas in the presence of Mg(2+)-ADP, maximal rigor tension developed to 143% of the control value; P(i) had no effect. The tension-to-stiffness (measured by the quick length-change technique) ratio was lower in rigor (no PCr and pMg(2+)-ATP 6) than during Ca2+ activation in the presence of both PCr and ATP. Compared with control rigor conditions, this parameter was unchanged by Mg(2+)-ADP and decreased by acidic pH, suggesting a proton-induced decrease in the amount of force per crossbridge. In addition to their known effects on active tension, Mg(2+)-ADP and protons affect rigor tension and influence ischemic contracture development. It is concluded that ischemic contracture and increased myocardial stiffness may be mediated by a decreased PCr and local Mg(2+)-ADP accumulation. This emphasizes the importance of myofibrillar creatine kinase activity in preventing ischemic contracture.
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PMID:Myocardial ischemic contracture. Metabolites affect rigor tension development and stiffness. 815 39

A new approach was used to study transient structural states of cross-bridges during activation of muscle fibers. Rabbit skinned muscle fibers were rapidly and synchronously activated from the rigor state by photolysis of caged ATP in the presence of Ca2+. At several different times during the switch from rigor to fully active tension development, the fibers were rapidly frozen on a liquid helium-cooled metal block, freeze-substituted, and examined in an electron microscope. The limits of structural preservation and resolution with this technique were analyzed. We demonstrate that the resolution of our images is sufficient to draw the following conclusions about cross-bridge structure. Rigor cross-bridges point away from the Z-line and most of them are wider near the thin filaments than near the backbone of the thick filaments. In contrast, cross-bridges in actively contracting fibers stretch between the thick and thin filaments at a variable angle, and are uniformly thin. Diffraction patterns computed from contracting muscle show layer lines both at 38 and 43 nm indicating that active cross-bridges contribute mass to both the actin- and myosin-based helical periodicities. The images obtained from fibers frozen 20 ms after release of ATP show a mixture of rigor and active type cross-bridge configurations. There is little evidence of cross-bridges with the rigor shape by 50 ms, and the difference in configurations between 50 and 300 ms after photolysis is surprisingly subtle.
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PMID:Flash and smash: rapid freezing of muscle fibers activated by photolysis of caged ATP. 836 45


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