Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8IXL6 (RNS)
 1,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 54-year-old neurotic patient developed pyridostigmine-induced proximal weakness with daily 3600 mg of pyridostigmine. Detailed analysis of the RNS test showed three different types of responses which were reproduced in the in vitro nerve-muscle preparation, confirming that three different responses represent the different degree of pyridostigmine toxicity. One of responses was a pattern, thought to be typical of anticholinesterase toxicity: repetitive discharge and the maximal decrement in the second response followed by an increment (dip phenomenon). With reduction of pyridostigmine, clinical and electrophysiological improvement followed.
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PMID:Pyridostigmine toxicity. Electrophysiological study. 822 30

With advancing age, skeletal muscle function declines as a result of strength loss. These strength deficits are largely due to reductions in muscle size (i.e., quantity) and its intrinsic force-producing capacity (i.e., quality). Age-induced reductions in skeletal muscle quantity and quality can be the consequence of several factors, including accumulation of reactive oxygen and nitrogen species (ROS/RNS), also known as oxidative stress. Therefore, the purpose of this mini-review is to highlight the published literature that has demonstrated links between aging, oxidative stress, and skeletal muscle quantity or quality. In particular, we focused on how oxidative stress has the potential to reduce muscle quantity by shifting protein balance in a deficit, and muscle quality by impairing activation at the neuromuscular junction, excitation-contraction (EC) coupling at the ryanodine receptor (RyR), and cross-bridge cycling within the myofibrillar apparatus. Of these, muscle weakness due to EC coupling failure mediated by RyR dysfunction via oxidation and/or nitrosylation appears to be the strongest candidate based on the publications reviewed. However, it is clear that age-associated oxidative stress has the ability to alter strength through several mechanisms and at various locations of the muscle fiber.
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PMID:Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality? 2719 56

Because of their contractile activity and their high oxygen consumption and metabolic rate, skeletal muscles continually produce moderate levels of reactive oxygen and nitrogen species (ROS/RNS), which increase during exercise and are buffered by multiple antioxidant systems to maintain redox homeostasis. Imbalance between ROS/RNS production and elimination results in oxidative stress (OxS), which has been implicated in ageing and in numerous human diseases, including cancer, diabetes or age-related muscle loss (sarcopenia). The study of redox homeostasis in muscle was hindered by its lability, by the many factors influencing technical OxS measures and by ROS/RNS important roles in signaling pathways and adaptative responses to muscle contraction and effort, which make it difficult to define a threshold between physiological signaling and pathological conditions. In the last years, new tools have been developed that facilitate the study of these key mechanisms, and deregulation of redox homeostasis has emerged as a key pathogenic mechanism and potential therapeutic target in muscle conditions. This is in particular the case for early-onset myopathies, genetic muscle diseases which present from birth or early childhood with muscle weakness interfering with ambulation and often with cardiac or respiratory failure leading to premature death. Inherited defects of the reductase selenoprotein N in SEPN1-related myopathy leads to chronic OxS of monogenic origin as a primary disease pathomechanism. In myopathies associated with mutations of the genes encoding the calcium channel RyR1, the extracellular matrix protein collagen VI or the sarcolemmal protein dystrophin (Duchenne Muscular Dystrophy), OxS has been identified as a relevant secondary pathophysiological mechanism. OxS being drug-targetable, it represents an interesting therapeutic target for these incurable conditions, and following preclinical correction of the cell or animal model phenotype, the first clinical trials with the antioxidants N-acetylcysteine (SEPN1- and RYR1-related myopathies) or epigallocatechin-gallate (DMD) have been launched recently. In this review, we provide an overview of the mechanisms involved in redox regulation in skeletal muscle, the technical tools available to measure redox homeostasis in muscle cells, the bases of OxS as a primary or secondary pathomechanism in early-onset myopathies and the innovative clinical trials with antioxidants which are currently in progress for these so-far untreatable infantile muscle diseases. Progress in our knowledge of redox homeostasis defects in these rare muscle conditions may be useful as a model paradigm to understand and treat other conditions in which OxS is involved, including prevalent conditions with major socioeconomic impact such as insulin resistance, cachexia, obesity, sarcopenia or ageing.
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PMID:Muscle redox disturbances and oxidative stress as pathomechanisms and therapeutic targets in early-onset myopathies. 2753 Oct 51

Skeletal muscle weakness is associated with oxidative stress and oxidative posttranslational modifications on contractile proteins. There is indirect evidence that reactive oxygen/nitrogen species (ROS/RNS) affect skeletal muscle myofibrillar function, although the details of the acute effects of ROS/RNS on myosin-actin interactions are not known. In this study, we examined the effects of peroxynitrite (ONOO-) on the contractile properties of individual skeletal muscle myofibrils by monitoring myofibril-induced displacements of an atomic force cantilever upon activation and relaxation. The isometric force decreased by ~50% in myofibrils treated with the ONOO- donor (SIN-1) or directly with ONOO-, which was independent of the cross-bridge abundancy condition (i.e., rigor or relaxing condition) during SIN-1 or ONOO- treatment. The force decrease was attributed to an increase in the cross-bridge detachment rate (gapp) in combination with a conservation of the force redevelopment rate (kTr) and hence, an increase in the population of cross-bridges transitioning from force-generating to non-force-generating cross-bridges during steady-state. Taken together, the results of this study provide important information on how ROS/RNS affect myofibrillar force production which may be of importance for conditions where increased oxidative stress is part of the pathophysiology.
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PMID:Force generated by myosin cross-bridges is reduced in myofibrils exposed to ROS/RNS. 3155 46

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and the presence of serum autoantibodies. In addition, skeletal muscle weakness is a common comorbidity that contributes to inability to work and reduced quality of life. Loss in muscle mass cannot alone account for the muscle weakness induced by RA, but instead intramuscular dysfunction appears as a critical factor underlying the decreased force generating capacity for patients afflicted by arthritis. Oxidative stress and associated oxidative post-translational modifications have been shown to contribute to RA-induced muscle weakness in animal models of arthritis and patients with RA. However, it is still unclear how and which sources of reactive oxygen and nitrogen species (ROS/RNS) that are involved in the oxidative stress that drives the progression toward decreased muscle function in RA. Nevertheless, mitochondria, NADPH oxidases (NOX), nitric oxide synthases (NOS) and phospholipases (PLA) have all been associated with increased ROS/RNS production in RA-induced muscle weakness. In this review, we aim to cover potential ROS sources and underlying mechanisms of oxidative stress and loss of force production in RA. We also addressed the use of antioxidants and exercise as potential tools to counteract oxidative stress and skeletal muscle weakness.
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PMID:Skeletal muscle redox signaling in rheumatoid arthritis. 3314 70