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      Role of accelerated aging in limb muscle wasting of patients with COPD

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          Abstract

          Purpose

          Skeletal muscle wasting is an independent predictor of health-related quality of life and survival in patients with COPD, but the complexity of molecular mechanisms associated with this process has not been fully elucidated. We aimed to determine whether an impaired ability to repair DNA damage contributes to muscle wasting and the accelerated aging phenotype in patients with COPD.

          Patients and methods

          The levels of phosphorylated H2AX (γH2AX), a molecule that promotes DNA repair, were assessed in vastus lateralis biopsies from 10 COPD patients with low fat-free mass index (FFMI; COPD L), 10 with preserved FFMI and 10 age- and gender-matched healthy controls. A panel of selected markers for cellular aging processes (CDKN2A/p16 ink4a, SIRT1, SIRT6, and telomere length) were also assessed. Markers of oxidative stress and cell damage and a panel of pro-inflammatory and anti-inflammatory cytokines were evaluated. Markers of muscle regeneration and apoptosis were also measured.

          Results

          We observed a decrease in γH2AX expression in COPD L, which occurred in association with a tendency to increase in CDKN2A/p16 ink4a, and a significant decrease in SIRT1 and SIRT6 protein levels. Cellular damage and muscle inflammatory markers were also increased in COPD L.

          Conclusion

          These data are in keeping with an accelerated aging phenotype as a result of impaired DNA repair and dysregulation of cellular homeostasis in the muscle of COPD L. These data indicate cellular degeneration via stress-induced premature senescence and associated inflammatory responses abetted by the senescence-associated secretory phenotype and reflect an increased expression of markers of oxidative stress and inflammation.

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          Most cited references 34

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          Characteristics of physical activities in daily life in chronic obstructive pulmonary disease.

          Quantification of physical activities in daily life in patients with chronic obstructive pulmonary disease has increasing clinical interest. However, detailed comparison with healthy subjects is not available. Furthermore, it is unknown whether time spent actively during daily life is related to lung function, muscle force, or maximal and functional exercise capacity. We assessed physical activities and movement intensity with the DynaPort activity monitor in 50 patients (age 64 +/- 7 years; FEV1 43 +/- 18% predicted) and 25 healthy elderly individuals (age 66 +/- 5 years). Patients showed lower walking time (44 +/- 26 vs. 81 +/- 26 minutes/day), standing time (191 +/- 99 vs. 295 +/- 109 minutes/day), and movement intensity during walking (1.8 +/- 0.3 vs. 2.4 +/- 0.5 m/second2; p < 0.0001 for all), as well as higher sitting time (374 +/- 139 vs. 306 +/- 108 minutes/day; p = 0.04) and lying time (87 +/- 97 vs. 29 +/- 33 minutes/day; p = 0.004). Walking time was highly correlated with the 6-minute walking test (r = 0.76, p < 0.0001) and more modestly to maximal exercise capacity, lung function, and muscle force (0.28 < r < 0.64, p < 0.05). Patients with chronic obstructive pulmonary disease are markedly inactive in daily life. Functional exercise capacity is the strongest correlate of physical activities in daily life.
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            Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice.

            In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity, and genome stability. Here we mutated the Sirt1 gene, a homolog of yeast Sir2, in mice to study its function. We show that a majority of SIRT1 null embryos die between E9.5 and E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrate that Sirt1(+/-);p53(+/-) mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis. Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity.
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              p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.

              Cellular senescence suppresses cancer by forcing potentially oncogenic cells into a permanent cell cycle arrest. Senescent cells also secrete growth factors, proteases, and inflammatory cytokines, termed the senescence-associated secretory phenotype (SASP). Much is known about pathways that regulate the senescence growth arrest, but far less is known about pathways that regulate the SASP. We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53. Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53. We show that diverse senescence-inducing stimuli activate the stress-inducible kinase p38MAPK in normal human fibroblasts. p38MAPK inhibition markedly reduced the secretion of most SASP factors, constitutive p38MAPK activation was sufficient to induce an SASP, and p53 restrained p38MAPK activation. Further, p38MAPK regulated the SASP independently of the canonical DDR. Mechanistically, p38MAPK induced the SASP largely by increasing NF-κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation--one that is necessary, sufficient, and independent of previously described pathways.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2018
                25 June 2018
                : 13
                : 1987-1998
                Affiliations
                [1 ]ELEGI Colt Laboratory, MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK, roberto.rabinovich@ 123456ed.ac.uk
                [2 ]Wolfson Wohl Translational Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
                [3 ]IDIBAPS, University of Barcelona, Barcelona, Spain
                [4 ]Respiratory Department, Royal Infirmary of Edinburgh, Edinburgh, UK, roberto.rabinovich@ 123456ed.ac.uk
                Author notes
                Correspondence: Roberto A Rabinovich, ELEGI Colt Laboratory, MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK, Tel +44 131 242 9198, Fax +44 131 242 6582, Email roberto.rabinovich@ 123456ed.ac.uk
                Article
                copd-13-1987
                10.2147/COPD.S155952
                6022820
                © 2018 Lakhdar et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Respiratory medicine

                apoptosis, copd, inflammation, aging, skeletal muscle wasting

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