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      Uremic myopathy: is oxidative stress implicated in muscle dysfunction in uremia?

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          Abstract

          Renal failure is accompanied by progressive muscle weakness and premature fatigue, in part linked to hypokinesis and in part to uremic toxicity. These changes are associated with various detrimental biochemical and morphological alterations. All of these pathological parameters are collectively termed uremic myopathy. Various interventions while helpful can't fully remedy the pathological phenotype. Complex mechanisms that stimulate muscle dysfunction in uremia have been proposed, and oxidative stress could be implicated. Skeletal muscles continuously produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) at rest and more so during contraction. The aim of this mini review is to provide an update on recent advances in our understanding of how ROS and RNS generation might contribute to muscle dysfunction in uremia. Thus, a systematic review was conducted searching PubMed and Scopus by using the Cochrane and PRISMA guidelines. While few studies met our criteria their findings are discussed making reference to other available literature data. Oxidative stress can direct muscle cells into a catabolic state and chronic exposure to it leads to wasting. Moreover, redox disturbances can significantly affect force production per se. We conclude that oxidative stress can be in part responsible for some aspects of uremic myopathy. Further research is needed to discern clear mechanisms and to help efforts to counteract muscle weakness and exercise intolerance in uremic patients.

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          Most cited references51

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          Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities.

          Logistic regression analysis was applied to a sample of more than 12,000 hemodialysis patients to evaluate the association of various patient descriptors, treatment time (hours/treatment), and various laboratory tests with the probability of death. Advancing age, white race, and diabetes were all associated with a significantly increased risk of death. Short dialysis times were also associated with high death risk before adjustment for the value of laboratory tests. Of the laboratory variables, low serum albumin less than 40 g/L (less than 4.0 g/dL) was most highly associated with death probability. About two thirds of patients had low albumin. These findings suggest that inadequate nutrition may be an important contributing factor to the mortality suffered by hemodialysis patients. The relative risk profiles for other laboratory tests are presented. Among these, low serum creatinine, not high, was associated with high death risk. Both serum albumin concentration and creatinine were directly correlated with treatment time so that high values for both substances were associated with long treatment times. The data suggest that physicians may select patients with high creatinine for more intense dialysis exposure and patients with low creatinine for less intense treatment. In a separate analysis, observed death rates were compared with rates expected on the basis of case mix for these 237 facilities. The data suggest substantial volatility of observed/expected ratios when facility size is small. Nonetheless, a minority of facilities (less than or equal to 2%) may have higher rates than expected when compared with the pool of all patients in this sample. The effect of various laboratory variables on mortality is substantial, while relatively few facilities have observed death rates that exceed their expected values. Therefore, we suggest that strategies designed to improve the overall mortality statistic for dialysis patients in the United States would be better directed toward improving the quality of care for all patients, particularly high-risk patients, within their usual treatment settings rather than trying to identify facilities with high death rate for possible regulatory intervention.
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            Reactive oxygen species: impact on skeletal muscle.

            It is well established that contracting muscles produce both reactive oxygen and nitrogen species. Although the sources of oxidant production during exercise continue to be debated, growing evidence suggests that mitochondria are not the dominant source. Regardless of the sources of oxidants in contracting muscles, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Further, oxidants regulate numerous cell signaling pathways and modulate the expression of many genes. This oxidant-mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species result in contractile dysfunction and fatigue. Ongoing research continues to explore the redox-sensitive targets in muscle that are responsible for both redox regulation of muscle adaptation and oxidant-mediated muscle fatigue. © 2011 American Physiological Society. Compr Physiol 1:699-729, 2011.
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              Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease.

              Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC(50) ∼1.2 nM) reversed the loss of body weight (≈5-7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38 ± 1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21 ± 1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                30 March 2015
                2015
                : 6
                : 102
                Affiliations
                [1] 1Department of Physical Education and Sport Sciences (DPESS), School of Physical Education (PE), University of Thessaly Trikala, Greece
                [2] 2Institute for Research and Technology-Centre for Research and Technology Hellas Trikala, Greece
                [3] 3Department of Surgery, Faculty of Medicine, University of Thessaly Larissa, Greece
                [4] 4Department of Nephrology, Faculty of Medicine, University of Thessaly Larissa, Greece
                Author notes

                Edited by: Brian McDonagh, University of Liverpool, UK

                Reviewed by: Laszlo Csernoch, University of Debrecen, Hungary; David Sheehan, University College Cork, Ireland; Brian McDonagh, University of Liverpool, UK

                *Correspondence: Christina Karatzaferi, Muscle Physiology and Mechanics Group, Department of Physical Education and Sport Sciences (DPESS), School of Physical Education (PE), University of Thessaly, Tmima Epistimis Fysikis Agogis kai Athlitismou - Panepistimio Thessalias, Karyes 42100, Trikala, Thessaly, Greece ck@ 123456pe.uth.gr

                This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2015.00102
                4378187
                25870564
                8347a739-71af-4af6-937a-a542360d7539
                Copyright © 2015 Kaltsatou, Sakkas, Poulianiti, Koutedakis, Tepetes, Christodoulidis, Stefanidis and Karatzaferi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 December 2014
                : 13 March 2015
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 56, Pages: 7, Words: 5131
                Categories
                Physiology
                Mini Review

                Anatomy & Physiology
                oxidative stress,uremia,muscle dysfunction,uremic myopathy,premature fatigue,muscle weakness

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