Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now well established that stromal interaction molecule 1 (STIM1) is the calcium sensor of endoplasmic reticulum stores required to activate store-operated calcium entry (SOC) channels at the surface of non-excitable cells. However, little is known about STIM1 in excitable cells, such as striated muscle, where the complement of calcium regulatory molecules is rather disparate from that of non-excitable cells. Here, we show that STIM1 is expressed in both myotubes and adult skeletal muscle. Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly. Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy. In addition, STIM1 haploinsufficiency confers a contractile defect only under conditions where rapid refilling of stores would be needed. These findings provide insight into the role of STIM1 in skeletal muscle and suggest that STIM1 has a universal role as an ER/SR calcium sensor in both excitable and non-excitable cells.
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PMID:STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. 1848 20

Autoantibodies impair acetylcholine receptor (AChR) in myasthenia gravis (MG) and P/Q-type voltage-gated calcium channel (VGCC) in Lambert-Eaton myasthenic syndrome (LEMS). (1) Some of MG and LEMS patients are "seronegative" for respective antibodies or modified by antibodies that recognize other proteins than AChR and VGCC such as MuSK, AChR allosteric site, membrane Na+ channel and ryanodine receptor-1 (RyR1) in MG, and synaptotagmin-1 in LEMS. (2) Autoimmune responses affect the proteins participating in the mechanisms to compensate for synaptic disorders on the basis of presynaptic Ca2+ homeostasis provided by VGCC and non-VGCC (receptor-operated TRPCs): they act as enhancers of Ca(2+) -mediated ACh release via phospholipase C signaling pathways including M1-type presynaptic muscarinic AChR, neurotrophin receptor (TrkB), and fast-mode of synaptic vesicle recycling. (3) The pathophysiology contributive to contractile fatigue in MG includes RyR1 and also TRPC3. The TRPC3 also forms a complex with STIM1 and Orail to make up for Ca2+ after sarcoplasmic Ca2+ release. The prevalent detection of anti-TRPC3 antibodies in MG with thymoma could affect muscle contractile machineries in addition to anti-RyR1-induced affection. (4) When one faces "seronegative" MG, one should be cautious to conformation-specific antibodies and also congenital myasthenic syndromes.
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PMID:[Recent advance in research for myasthenia gravis, in relation to various antibodies affecting synaptic structure and function]. 2003 Feb 11

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.
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PMID:Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome. 2504 82

Orai1 is a transmembrane protein that forms homomeric, calcium-selective channels activated by stromal interaction molecule 1 (STIM1) after depletion of intracellular calcium stores. In adult skeletal muscle, depletion of sarcoplasmic reticulum calcium activates STIM1/Orai1-dependent store-operated calcium entry. Here, we used constitutive and inducible muscle-specific Orai1-knockout (KO) mice to determine the acute and long-term developmental effects of Orai1 ablation on muscle structure and function. Skeletal muscles from constitutive, muscle-specific Orai-KO mice exhibited normal postnatal growth and fiber type differentiation. However, a significant reduction in fiber cross-sectional area occurred by 3 mo of age, with the most profound reduction observed in oxidative, fatigue-resistant fiber types. Soleus muscles of constitutive Orai-KO mice exhibited a reduction in unique type I fibers, concomitant with an increase in hybrid fibers expressing both type I and type IIA myosins. Additionally, ex vivo force measurements showed reduced maximal specific force and in vivo exercise assays revealed reduced endurance in constitutive muscle-specific Orai-KO mice. Using tamoxifen-inducible, muscle-specific Orai-KO mice, these functional deficits were found to be the result of the delayed fiber changes resulting from an early developmental loss of Orai1 and not the result of an acute loss of Orai1-dependent store-operated calcium entry.-Carrell, E. M., Coppola, A. R., McBride, H. J., Dirksen, R. T. Orai1 enhances muscle endurance by promoting fatigue-resistant type I fiber content but not through acute store-operated Ca2+ entry.
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PMID:Orai1 enhances muscle endurance by promoting fatigue-resistant type I fiber content but not through acute store-operated Ca2+ entry. 2758 68

The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.
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PMID:A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. 2922 74

STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions.This article has an associated First Person interview with Celia Cordero-Sanchez, co-first author of the paper.
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PMID:A luminal EF-hand mutation in STIM1 in mice causes the clinical hallmarks of tubular aggregate myopathy. 3166 34

Store-operated calcium entry (SOCE) plays a pivotal role in skeletal muscle physiology as, when impaired, the muscle is prone to early fatigue and the development of different myopathies. A chronic mode of slow SOCE activation is carried by stromal interaction molecule 1 (STIM1) and calcium-release activated channel 1 (ORAI1) proteins. A phasic mode of fast SOCE (pSOCE) occurs upon single muscle twitches in synchrony with excitation-contraction coupling, presumably activated by a local and transient depletion at the terminal cisternae of the sarcoplasmic reticulum Ca2+-stores. Both SOCE mechanisms are poorly understood. In particular, pSOCE has not been described in detail because the conditions required for its detection in mouse skeletal muscle have not been established to date. Here we report the first measurements of pSOCE in mouse extensor digitorum longus muscle fibers using electrical field stimulation (EFS) in a skinned fiber preparation. We show moderate voluntary wheel running to be a prerequisite to render muscle fibers reasonably susceptible for EFS, and thereby define an experimental paradigm to measure pSOCE in mouse muscle. Continuous monitoring of the physical activity of mice housed in cages equipped with running wheels revealed an optimal training period of 5-6 days, whereby best responsiveness to EFS negatively correlated with running distance and speed. A comparison of pSOCE kinetic data in mouse with those previously derived from rat muscle demonstrated very similar properties and suggests the existence and similar function of pSOCE across mammalian species. The new technique presented herein enables future experiments with genetically modified mouse models to define the molecular entities, presumably STIM1 and ORAI1, and the physiological role of pSOCE in health and under conditions of disease.
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PMID:Phasic Store-Operated Ca2+ Entry During Excitation-Contraction Coupling in Skeletal Muscle Fibers From Exercised Mice. 3326 6