Editorial
Skeletal Muscle Dysfunction in COPD: Novelties in the Last Decade
Disfunción de la musculatura esquelética en la EPOC: novedades de la última década
a Servicio de Neumología-Debilidad muscular y caquexia en las enfermedades respiratorias crónicas y el cáncer de pulmón, IMIM-Hospital del Mar, Barcelona, Spain
b Departament de Ciències Experimentals i de la Salut (CEXS), Universitat Pompeu Fabra (UPF), Parc de Recerca Biomédica de Barcelona (PRBB), Barcelona, Spain
c Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain
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Muscle dysfunction negatively affects exercise capacity in these patients, thus diminishing their quality of life. Furthermore, muscle dysfunction and wasting of the lower limbs has been shown to predict disease morbidity and mortality regardless of the airway obstruction.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1–3</span></a> Several factors and biological mechanisms are involved in the multifactorial etiology of muscle dysfunction in COPD.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> Interestingly, while both respiratory and peripheral muscles are disturbed in these patients, the latter are usually more severely affected, and have been the subject of abundant research in the last two decades. Evidence has also shown that several cellular and molecular events are differentially expressed in the respiratory and limb muscles of patients with COPD. This editorial aims to provide an overview of the most relevant biological mechanisms that have so far been shown to participate in the pathophysiology of lower limb muscle dysfunction in patients with COPD.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In the last two decades, several advances have been made in the identification of the biological mechanisms underlying muscle dysfunction in COPD. An understanding of the most relevant contributing mechanisms in this condition will help clinicians design therapeutic strategies that will alleviate muscle mass loss and dysfunction in patients with COPD. An increase in oxidative stress, as measured by protein oxidation levels, has been demonstrated repeatedly in the limb muscles of patients with COPD.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> Moreover, oxidative stress markers were also shown to inversely correlate with clinical parameters, such as exercise capacity, body composition, and quadriceps strength inpatients with COPD.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> These results suggest that oxidative events may hamper muscle function by altering key cellular processes involved in muscle contraction. Indeed, the content of several specific muscle proteins such as creatine kinase and myosin heavy chain was reduced in the vastus lateralis of patients with severe COPD and muscle wasting, while increased levels of oxidation was detected in the same proteins.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">5–7</span></a> Systemic levels of oxidative stress have also been demonstrated in patients with COPD.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Several markers of the ubiquitin-proteasome system were consistently upregulated in the lower limb muscles of COPD patients.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,6,7</span></a> Moreover, the number of autophagosomes and the expression of other autophagy markers were also increased in the vastus lateralis of patients with severe COPD and muscle mass loss.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,7,9</span></a> Importantly, several redox signaling cellular pathways such as nuclear factor (NF)-κB, forkhead box (FoxO)1 and FoxO3 are likely to mediate the loss of muscle mass in patients with severe COPD and cachexia.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6,7</span></a> Increased levels of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei were also seen in the vastus lateralis of severe COPD patients with normal body composition, whereas muscle levels of ultrastructural apoptosis were low and did not differ from those detected in healthy controls.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Epigenetic control of cells, defined as the process whereby gene expression is regulated by heritable mechanisms that do not affect DNA sequence, has recently emerged as a potential biological mechanism that may regulate muscle function and mass in COPD. The epigenetic modifications identified so far in cells are the following: (1) DNA methylation, (2) histone acetylation, (3) histone methylation, and (4) non-coding RNAs such as microRNAs. The epigenetic events modify gene transcription in different ways, for example, DNA methylation at the 5 position of cytosine specifically reduces gene expression. Acetylation is a transient, enzymatically controlled biochemical process, and is the most common posttranslational modification of histones. Acetylation, a process mediated by histone acetyltransferases (HTA), results in a rather open chromatin structure that is transcriptionally active, while deacetylation, through the action of histone deacetylases (HDAC), blocks transcription. Additionally, methylation of histones may activate or repress gene transcription, depending on the proteins recruited to the chromatin.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Evaluation of the expression of microRNAs has recently attracted much attention in the study of the etiology of respiratory diseases. MicroRNAs, encoded by eukaryotic nuclear DNA, are non-coding single-stranded RNA molecules (18–24 nucleotides) that function in the post-transcriptional regulation of gene expression. Interestingly, they exert their action via base-pairing with complementary sequences in mRNA molecules that result in gene silencing via translational repression or target degradation. MicroRNAs may have different mRNA targets, and a given mRNA may also be targeted by multiple microRNAs. MicroRNAs regulate many physiological cellular processes, and may play a significant role in the pathogenesis of several lung diseases including lung cancer and COPD.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Recently, several studies have focused on the analysis of epigenetic modifications in the muscles of COPD patients. As such, in patients with mild COPD, miR-1 expression was increased and positively correlated with airway obstruction and quadriceps force.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a> Importantly, the expression of miR-1, miR-206, and miR-27a, levels of lysine-acetylated proteins and histones, and acetylated histone 3 were increased in the quadriceps of COPD patients, especially in those with muscle weakness and wasting, while expression of HDAC3, HDAC4, and sirtuin-1 were reduced.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> In other experiments, levels of miR-1 levels were lower, while those of HDAC4 were higherin the vastus lateralis of COPD patients with preserved body composition.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> Furthermore, levels of the transcription factor Yin Yang (YY)1, which modifies histones, inversely correlated with the size of slow- and fast-twitch fibers in the limb muscles of COPD patients with normal body composition.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> Interestingly, systemic levels of muscle-specific microRNAs were also upregulated in patients with severe COPD and normal body composition.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> In summary, several epigenetic events that are differentially expressed in the limb muscles of COPD patients with and without muscle mass loss may counterbalance the underlying mechanisms that deteriorate their muscle mass and function.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Further research is still required in order to identify additional mechanisms that may also underlie the etiology of skeletal muscle dysfunction in patients with COPD. We need to identify new cellular and molecular mechanisms that can be specifically targeted using pharmacological strategies and/or exercise modalities to prevent skeletal muscle from undergoing further functional deterioration and wasting.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of Interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The author has no conflict of interest relating to this manuscript</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Barreiro E. Disfunción de la musculatura esquelética en la EPOC: novedades de la última década. Arch Bronconeumol. 2017;53:43–44.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Marquis" 1 => "R. Debigare" 2 => "Y. Lacasse" 3 => "P. LeBlanc" 4 => "J. Jobin" 5 => "G. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 48 | 28 | 76 |
| 2024 September | 51 | 26 | 77 |
| 2024 August | 87 | 57 | 144 |
| 2024 July | 45 | 25 | 70 |
| 2024 June | 71 | 43 | 114 |
| 2024 May | 89 | 35 | 124 |
| 2024 April | 45 | 25 | 70 |
| 2024 March | 43 | 20 | 63 |
| 2024 February | 36 | 24 | 60 |
| 2023 March | 19 | 2 | 21 |
| 2023 February | 75 | 21 | 96 |
| 2023 January | 45 | 35 | 80 |
| 2022 December | 75 | 41 | 116 |
| 2022 November | 89 | 44 | 133 |
| 2022 October | 63 | 47 | 110 |
| 2022 September | 68 | 26 | 94 |
| 2022 August | 102 | 54 | 156 |
| 2022 July | 100 | 42 | 142 |
| 2022 June | 62 | 31 | 93 |
| 2022 May | 117 | 53 | 170 |
| 2022 April | 104 | 33 | 137 |
| 2022 March | 133 | 42 | 175 |
| 2022 February | 80 | 24 | 104 |
| 2022 January | 113 | 37 | 150 |
| 2021 December | 67 | 41 | 108 |
| 2021 November | 104 | 39 | 143 |
| 2021 October | 71 | 55 | 126 |
| 2021 September | 88 | 42 | 130 |
| 2021 August | 67 | 63 | 130 |
| 2021 July | 60 | 41 | 101 |
| 2021 June | 91 | 45 | 136 |
| 2021 May | 76 | 43 | 119 |
| 2021 April | 283 | 129 | 412 |
| 2021 March | 139 | 21 | 160 |
| 2021 February | 112 | 32 | 144 |
| 2021 January | 99 | 18 | 117 |
| 2020 December | 88 | 27 | 115 |
| 2020 November | 89 | 16 | 105 |
| 2020 October | 105 | 18 | 123 |
| 2020 September | 74 | 11 | 85 |
| 2020 August | 83 | 13 | 96 |
| 2020 July | 103 | 29 | 132 |
| 2020 June | 118 | 13 | 131 |
| 2020 May | 82 | 15 | 97 |
| 2020 April | 92 | 27 | 119 |
| 2020 March | 87 | 27 | 114 |
| 2020 February | 89 | 19 | 108 |
| 2020 January | 85 | 33 | 118 |
| 2019 December | 94 | 19 | 113 |
| 2019 November | 71 | 31 | 102 |
| 2019 October | 60 | 17 | 77 |
| 2019 September | 60 | 20 | 80 |
| 2019 August | 44 | 17 | 61 |
| 2019 July | 72 | 26 | 98 |
| 2019 June | 37 | 13 | 50 |
| 2019 May | 91 | 16 | 107 |
| 2019 April | 101 | 30 | 131 |
| 2019 March | 77 | 27 | 104 |
| 2019 February | 74 | 14 | 88 |
| 2019 January | 65 | 17 | 82 |
| 2018 December | 56 | 4 | 60 |
| 2018 November | 63 | 20 | 83 |
| 2018 October | 109 | 31 | 140 |
| 2018 September | 33 | 9 | 42 |
| 2018 May | 26 | 0 | 26 |
| 2018 April | 44 | 6 | 50 |
| 2018 March | 55 | 10 | 65 |
| 2018 February | 62 | 11 | 73 |
| 2018 January | 102 | 14 | 116 |
| 2017 December | 64 | 16 | 80 |
| 2017 November | 24 | 9 | 33 |
| 2017 October | 35 | 9 | 44 |
| 2017 September | 24 | 10 | 34 |
| 2017 August | 26 | 22 | 48 |
| 2017 July | 29 | 18 | 47 |
| 2017 June | 37 | 35 | 72 |
| 2017 May | 47 | 20 | 67 |
| 2017 April | 0 | 1 | 1 |
| 2017 February | 1 | 1 | 2 |
| 2016 December | 0 | 1 | 1 |
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