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Epigenetics and muscle dysfunction in chronic obstructive pulmonary disease ESTHER BARREIRO, and JOAQUIM GEA BARCELONA AND MADRID, SPAIN

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease and a major leading cause of morbidity and mortality worldwide. In COPD, comorbidities, acute exacerbations, and systemic manifestations negatively influence disease severity and progression regardless of the respiratory condition. Skeletal muscle dysfunction, which is one of the commonest systemic manifestations in patients with COPD, has a tremendous impact on their exercise capacity and quality of life. Several pathophysiological and molecular underlying mechanisms including epigenetics (the process whereby gene expression is regulated by heritable mechanisms that do not affect DNA sequence) have been shown to participate in the etiology of COPD muscle dysfunction. The epigenetic modifications identified so far in cells include DNA methylation, histone acetylation and methylation, and noncoding RNAs such as microRNAs. Herein, we first review the role of epigenetic mechanisms in muscle development and adaptation to environmental factors in several models. Moreover, the epigenetic events reported so far to be potentially involved in muscle dysfunction and mass loss of patients with COPD are also discussed. Furthermore, the different expression profile of several muscleenriched microRNAs in the diaphragm and vastus lateralis muscles of patients with COPD are also reviewed from results recently obtained in our group. The role of protein hyperacetylation in enhanced muscle protein catabolism of limb muscles is also discussed. Future research should focus on the full elucidation of the triggers of epigenetic mechanisms and their specific downstream biological pathways in COPD muscle dysfunction and wasting. (Translational Research 2014;-:1–12) Abbreviations: -- ¼ ---

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From the Respiratory Medicine Department-Muscle and Respiratory System Research Unit, Institute of Medical Research of Hospital del Mar (IMIM)-Hospital del Mar, Parc de Salut Mar, Barcelona Biomedical Research Park (PRBB), Barcelona, Spain; Centro de Investigaci on en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Conflict of interests: None.

Submitted for publication February 9, 2014; revision submitted April 2, 2014; accepted for publication April 8, 2014.

Editorial support: None.

Ó 2014 Mosby, Inc. All rights reserved.

This study has been supported by CIBERES, FIS 11/02029, FIS 12/ 02534, SAF-2011-26908, 2009-SGR-393, SEPAR 2010, FUCAP 2011, FUCAP 2012, and Marato TV3 (MTV3-07-1010) (Spain).

http://dx.doi.org/10.1016/j.trsl.2014.04.006

Reprint requests: Esther Barreiro, Pulmonology Department and Lung Cancer Research Group, IMIM-Hospital del Mar, PRBB, Dr Aiguader, 88, E-08003 Barcelona, Spain; e-mail: ebarreiro@ imim.es. 1931-5244/$ - see front matter

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INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease and a major leading cause of morbidity and mortality worldwide.1 COPD is characterized by persistent progressive airflow limitation together with an enhanced chronic inflammatory response to noxious particles or gases, usually inhaled cigarette smoke, in the airways and lungs of the patients. Most of these patients very often have concomitant diseases known as comorbidities, which significantly impair their quality of life. Acute exacerbations are also common in patients with COPD. They have a substantial impact on the patients’ quality of life, especially because of the reported loss of muscle mass and bone mineral density after hospital discharge for COPD acute exacerbations.1-3 Moreover, besides respiratory symptoms, the function of other organs such as bones, the cardiovascular system, and skeletal muscles may also be altered in COPD. Taken together, comorbidities, acute exacerbations, and systemic manifestations negatively influence disease severity and progression regardless of the respiratory condition in COPD.1-3 Skeletal muscle dysfunction, which is one of the commonest systemic manifestations in patients with COPD, has a tremendous impact on their exercise capacity. Several cellular and molecular mechanisms have been shown to underlie the etiology of COPD muscle dysfunction. In the last few years, the role of epigenetics has also emerged as a relevant mechanism potentially involved in muscle mass maintenance and performance in several models including COPD.4,5 Specifically, the present article encompasses several sections in which the following topics have been reviewed: skeletal muscle dysfunction in COPD, types of epigenetic mechanisms, epigenetic regulation of muscle development and adaptation, the presence of epigenetic events in muscles and blood in COPD, and the differential expression profile of epigenetic mechanisms in respiratory and limb muscles of COPD patients with different disease severity. Skeletal muscle dysfunction in COPD. COPD is a highly prevalent condition that imposes a significant economic burden worldwide as a consequence of acute exacerbations and comorbidities. In patients with COPD, skeletal muscle dysfunction is a common systemic manifestation that affects both respiratory and limb muscles,6 resulting in a significant impairment of their quality of life. Quadriceps muscle dysfunction appears in one-third of the patients, even at very early stages of the disease when severe airway obstruction has not yet developed.7 Additionally, quadriceps weakness, defined as reduced muscle strength, and lower muscle mass as measured by mid-thigh cross-sectional area were also shown to be

Fig 1. Schematic representation of skeletal muscle dysfunction in patients with COPD. Systemic and local factors through the action of biological (cellular and molecular) mechanisms including epigenetics underlie the etiology of muscle dysfunction and muscle mass loss in COPD. In this context, muscle phenotype and performance of the muscles will impair in the patients. Muscle mass and function loss, which negatively influence exercise tolerance and quality of life in the patients, are prognostic factors in COPD, because they predict survival. COPD, chronic obstructive pulmonary disease.

good predictors of COPD mortality.8,9 Skeletal muscle dysfunction in patients with COPD is characterized by reduced muscle strength and endurance, probably because of the interaction of different systemic and local factors, which act through different biological mechanisms (Fig 1). Skeletal muscle dysfunction in COPD is also highly dependent on the specific function of the muscle.10 In this regard, in patients with severe COPD, the mechanical loads imposed by the respiratory system, which modify the resting length of the diaphragm, play a major role in their respiratory muscle dysfunction. Additionally, biological and structural factors are also involved in the pathophysiology of respiratory muscle dysfunction in patients with COPD, although to a lesser extent to their recognized effects on the lower limb muscles.10,11 In general, lower limb muscles are more adversely affected than inspiratory muscles, probably because of disuse or deconditioning.12 As the limb muscles do not have to contract at a specific length, biological and structural factors are the main players of peripheral muscle dysfunction in patients with COPD (Fig 1). For instance, the vastus lateralis muscle of patients with severe COPD consistently exhibits a slow-to-fast fiber-type switch.10,13,14 Atrophy of fasttwitch fibers has also been reported in the peripheral muscles of patients with severe COPD with nutritional abnormalities and significant muscle wasting.14

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Table I. Epigenetic mechanisms in cells DNA methylation

Histone acetylation

Histone methylation

MicroRNAs

Addition of a methyl group to 50 -cytosine before guanine in the same chain (CpG islands)

Acetylation: acetyl group from acetyl-CoA transferred to lysine residues 0 euchromatin 0 favors transcription Deacetylation: reverses acetylation 0 heterochromatin 0 blocks transcription

Addition of methyl groups to lysine (33) & arginine (32) residues 0 may favor or block transcription

Noncoding single-stranded RNA molecules 0 posttranscriptional regulation of gene expression Base pairing with complementary sequences in mRNA molecules 0 gene silencing (translational repression or target degradation)

Abbreviations: DNA, deoxyribonucleic acid; RNA, ribonucleic acid.

Interestingly, in the diaphragms of patients with COPD with a wide range of disease severity, atrophy of all fiber types was also described in previous studies.10,15 In this regard, reduced levels of contractile myosin heavy chain (MyHC) protein and increased protein degradation via the ubiquitin-proteasome pathway were also shown in the diaphragm16-18 and vastus lateralis muscles14 of patients with COPD. Several factors and biological mechanisms have been shown to participate in the multifactorial etiology of COPD muscle dysfunction. Deconditioning, nutritional abnormalities, muscle mass loss, systemic inflammation, oxidative stress, and cellular alterations that affect muscle structure are among the most relevant contributing factors and mechanisms, as shown in many articles and investigations conducted in the last decade.9-11,13-16,19-51 Epigenetic control, defined as the process whereby gene expression is regulated by heritable mechanisms that do not affect DNA sequence, has also emerged as a potential biological mechanism that may regulate muscle function and mass in COPD.5,32 Epigenetic events reported so far to be potentially involved in the etiology of muscle dysfunction and mass loss in COPD are discussed subsequently in the review.5,32 In patients with COPD, the different epigenetic mechanisms could play a relevant role in their loss of muscle mass and function, through alterations in several biological pathways (Fig 1). The present article represents an update of a previously published review by members in our group.24 Q4

Epigenetic regulation concepts. Genomic DNA is

in

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condensed in the form of chromatin within the nucleus in eukaryote cells. Chromatin is composed of nucleosomes and a core of histone proteins (H2A, H2B, H3, and H4). Accessibility to DNA is reduced when chromatin is packed in the nucleus. As such, gene transcription may only occur when DNA-histone interaction is weaker, facilitating the access of transcription factors to DNA. The stability of the nucleosomes and protein-protein interactions that modify the transcriptional activity of the DNA

is regulated by several epigenetic mechanisms such as DNA and histone methylation processes and acetylation.52 The epigenetic DNA modifications include DNA methylation, covalent histone modifications, noncovalent mechanisms, namely, incorporation of histone variants and nucleosome remodeling, and noncoding RNAs including microRNAs.53 These different molecular mechanisms are briefly described subsequently. DNA methylation. DNA methylation is a biochemical process that involves the addition of a methyl group (CH3) to the 5 position of the cytosine that stands directly before a guanine molecule in the same chain. It usually occurs in the CpG islands, a CG rich region where C and G are connected by a phosphodiester bond (Table I). This reaction is mediated by methyltransferases and can be inherited through cell division. DNA methylation is the most stable modification of the chromatin structure and may vary at different time points in life such as during development and aging. DNA methylation at the 5 position of cytosine specifically reduces gene expression. Importantly, the pattern of DNA methylation may also vary in response to environmental factors.53,54 Histone acetylation. Acetylation is a transient, enzymatically controlled biochemical process, and the commonest post-translational modification of histones. The acetyl group from acetyl-CoA is transferred to a lysine residue, thus converting its basic side chain into a neutral residue (Table I). This modification results in a structural change of the histone tail that alters the interaction between histones and DNA as well as the associations with the nucleosomes. These alterations result in a rather open chromatin (euchromatin) structure that is transcriptionally active (Table I). Deacetylation reverses this process, leading to a closed chromatin structure (heterochromatin) that is transcriptionally blocked (Table I). As acetylation also regulates protein-protein interactions, acetyl-lysine residues could recruit proteins to specific regions of the chromatin to further activate transcription.

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Histone acetyltransferases (HTAs) and 18 known human histone deacetylases (HDACs), grouped into 4 classes (I, IIA, IIB, III or Sirtuins in mammals, and IV), modulate lysine acetylation in a dynamic fashion. Sirtuins serve as class III HDACs by removing acetylases coupled with NAD hydrolysis at histone tails and also play a relevant role in aging, stress, and apoptosis.54 Moreover, HDACs, which do not directly bind DNA, may also interact with chromatin through association with other histone-modifying proteins and transcription factors. HTAs are activated on phosphorylation that leads to a shift in the balance from HDACs to HTAs within the nucleus, to the acetylation of specific histones, and to an increase in gene transcription. In fact, acetylation is now being considered as a biological process that is far beyond chromatin remodeling, as it may participate in metabolic control, muscle wasting conditions, and aging.4 Also, it has been proposed that lysine hyperacetylation of transcription factors and nuclear cofactors involved in gene transcription regulation influence muscle mass.4 Several studies have shown that acetylation of lysine residues promotes the degradation of proteins in muscles leading to muscle wasting, as briefly described subsequently. One possible mechanism could be the activation of transcription factors and proteins by lysine acetylation that regulate genes involved in muscle mass loss.4,55 The fact that several HTAs may also exert ubiquitin ligase and polyubiquitination activities on muscle proteins appears as another potential mechanism of hyperacetylation-induced muscle wasting.4,56 Additionally, individual HTAs and HDACs can form complexes with different enzymes that regulate protein ubiquitination, probably through the stimulation of the activity of ubiquitin ligases.4,57 Finally, acetylation of the chaperone HSP90, which stabilizes multiple cellular proteins, was shown to negatively influence its protective effects, thus leading to increased degradation of HSP90-interacting proteins.4,58 Eventually, in several models of muscle wasting including experimental sepsis, the expression of HDAC3, HDAC6, and SIRT1 was shown to be reduced, which further led to a decrease in total HDAC activity within the skeletal muscles.4 Histone methylation. Methylation of histones may take place at both lysine and arginine residues, which accept 3 and 2 methyl groups, respectively (Table I). Distinct from acetylation, methylation does not modify the charge of arginine and lysine; thus, it does not alter chromatin folding. Gene transcription may be activated or repressed by methyllysine or methylarginine depending on the proteins recruited to the chromatin. For instance, methyllysine binds proteins that contain chromodomains59 or plant homeodomains,60 whereas both

methyllysine and methylarginine are recognized by proteins containing Tudor domains, which are conserved protein structural motifs.61,62 MicroRNAs. MicroRNAs, encoded by eukaryotic nuclear DNA, are noncoding single-stranded RNA molecules (18–24 nucleotides) that function in the posttranscriptional regulation of gene expression (Table I). They exert their action via base pairing with complementary sequences in mRNA molecules that result in gene silencing via translational repression or target degradation (Table I). MicroRNAs may have different mRNA targets, and in a similar manner, a given mRNA may also be targeted by multiple microRNAs. MicroRNAs regulate many cellular processes and appear to have a role in the pathogenesis of lung diseases such as lung cancer, pulmonary fibrosis, asthma, and COPD.63 The biogenesis of microRNAs is rather complex and encompasses several steps. RNA polymerase II transcribes long transcripts known as primary microRNAs. They are then processed by a nuclear multiprotein complex that contains Drosha and DGR8/Pasha, leading to the formation of precursor microRNAs (pre-microRNAs) with stem-loop structures.64,65 These pre-microRNAs are then transported into the cytoplasm by the nucleocytoplasmic shuttle exporting-5, where they become substrates of RNase III enzyme Dicer to generate 22-nucleotide miRNA duplexes.66 Subsequently, microRNAs assemble together with Argonaute proteins to form the RNA-induced silencing complex (RISC or miRISC), which contains Dicer and many associated proteins67,68 (Fig 2). The mature microRNA is part of an active RISC containing Dicer and many associated proteins, which with incorporated microRNAs is known as miRISC. This complex silences specific target genes by base pairing with the 30 untranslated region of their target mRNAs, which may result in mRNA degradation if the pairing is perfect or in inhibition of translation when the pairing is not complete.67,68 Mechanisms of action of epigenetic events in skeletal muscles. Importantly, epigenetic regulation appears to

play a crucial role in muscle development. In keeping with, in muscle satellite cells, epigenetic events regulate quiescence and proliferation states preventing their differentiation. As such, DNA methylation acts as a major repressive mechanism of muscle satellite cell differentiation.69,70 On the contrary, demethylation together with myoD and myogenin are required for the initiation of the differentiation program in muscle satellite cells.71,72 Other repressive mechanisms shown to act on chromatin-associated histones also control muscle satellite quiescence and proliferation. In proliferating myoblasts, HDAC1, HDAC2, HDAC3, HDAC4, and HDAC5, and Sirtuins maintain transcription factors in

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Fig 2. Mean and standard deviations corresponding to the levels of expression of different muscle-enriched microRNAs (A and B) within the diaphragm muscle of healthy nonsmoker control subjects and patients with mild-to-moderate COPD separately. Significant differences in the levels of the different microRNAs in the muscles of each study group independently were obtained after using an analysis of variance test for repeated measures with a Bonferroni’s multiple comparison correction. Values for each of the microRNA levels within each study group were represented with the same letter. Values with the same letter are not statistically different. COPD, chronic obstructive pulmonary disease; miR, microRNA.

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a deacetylated state, especially in the absence of differentiation-promoting signals. Other epigenetic mechanisms such as the replacement of canonical histones with histone variants or the expression of specific histone isoforms in a cell-state or cell-type manner may also regulate muscle satellite quiescence and proliferation.65 Although still unclear, epigenetic mechanisms also seem to regulate the muscle differentiation gene program. The repressive scenario is quickly modified by the differentiation-promoting signals. For instance, it has been shown that genes actively transcribing are marked by H3K4me3, whereas those ready to start transcription are tagged by H3K4me2.73 Moreover, Pax7 binds to H3K4me2 regulatory elements in target genes such as Myf5 in satellite cells.74,75 This binding leads to the recruitment of TRxG histone methyltransferase complex, which in turn, will induce strong H3K4 trimethylation on the transcription start site, thus

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establishing a transcriptionally active domain.74,75 Finally, the muscle differentiation program will proceed on the activation of transcription factors and nucleosomes via the inactivation of HDACs and Sirtuins together with the concomitant activation of HTAs. Q10 Importantly, microRNAs also seem to play a paramount role during muscle development. Although most of the microRNAs identified so far regulate different processes in several tissues, some microRNAs are tissue specific. For example, miR-1, miR-133, and miR-206 are abundantly expressed within skeletal muscles and are identified as muscle-specific microRNAs (myomiRs). These microRNAs exert several functions in skeletal muscles and are crucial to different stages of muscle development. Inactivation of Dicer, which leads to the accumulation of unprocessed pre-miRNAs, results in perinatal lethality, reduced muscle mass, and abnormal myofiber structure.68 Importantly, miR-1 and miR-133, which are localized within the same chromosomal loci and transcribed together, become 2 independent mature miRNAs with completely different biological functions in the regulation of skeletal muscle proliferation and differentiation. Although miR-1 promotes muscle cell differentiation by targeting HDAC4, miR-133 stimulates myoblast proliferation by repressing the serum response factor (SRF), whereas inhibiting myotube formation.76 In a similar fashion to miR-1, miR-206 promotes myotube formation by targeting the p180 subunit of DNA polymerase alpha. This leads to the inhibition of DNA synthesis and cell cycle withdrawal, as well as to terminal cell differentiation.69,70 Moreover, miR-1 was also shown to target the insulin-like growth factor 1 (IGF-1) pathway and to exert a feedback loop between miR-1 expression and the IGF-1 signal transduction cascade.77 Additionally, the innervation process of the muscle fibers also seems to be regulated by miR-1 and miR-206 through the downregulation of connexin 43-dependent gap junctional communication.78 Other microRNAs ubiquitously expressed in tissues are also abundantly expressed in muscles and may regulate skeletal muscle development and phenotype. For instance, miR-206 and miR-486 were shown to induce myoblast differentiation through the downregulation of paired box protein (Pax)7.79 Therefore, expression of these 2 microRNAs favors differentiation in myoblasts, whereas inhibition of their expression results in the maintenance of Pax7 activity, thus delaying differentiation. A target of Pax3, miR-27, is also expressed in embryonic myotomes, satellite cells, and adult muscle fibers.80 Satellite cells enter the myogenic differentiation program when Pax3 is targeted by miR-27. MyoD may also be induced by miR-181, which targets the repressor of myoblast terminal differentiation

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Table II. Epigenetic events in muscles and blood of patients with COPD with different disease severity and body composition Types of muscles

Mild-to-moderate COPD

Vastus lateralis

[ Muscle-enriched microRNA levels (unpublished observations)

Diaphragm

[ Muscle-enriched microRNA levels, [ HDAC levels (unpublished observations)

Blood

Severe COPD, preserved body composition

Y miR-1, [ HDAC4, & Y MRTF/SRF (Lewis et al5) [ muscle-enriched microRNA levels (unpublished observations)

Severe COPD, muscle wasting

Y Muscle-enriched microRNA levels, [ total acetyl-lysine protein levels, Y HDAC levels (unpublished observations)

[ miR-1, [ miR-499, [ miR-181, [ miR-133, [ miR-206 (Donaldson et al32)

Abbreviations: COPD, chronic obstructive pulmonary disease; HADC, histone deacetylase; miR, microRNA; MRTF/SFR, myocardin-related transcription factors and serum response factor; RNA, ribonucleic acid.

Hox-A11.81 Muscle development is also favored by the action of miR-29 through the feedback inhibition of the transcriptional regulator Yin Yang (YY)1.82 Another study demonstrated that loss of miR-29 induces the transdifferentiation of myoblasts into myofibroblasts, whereas transforming growth factor beta signaling negatively regulates its expression.83 Moreover, in the same study, miR-29 expression was shown to decrease in dystrophic muscles from mdx mice (an experimental model of Duchenne muscular dystrophy).83 Moreover, muscle-specific transcription factors such as myoD, myogenin, myocyte-enhancing factor (MEF)2, and the SRF may also regulate the expression of myomiR genes.84,85 Epigenetic control of muscle adaptation to environmental factors. As sedentarism and decondition-

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ing are probably the main contributing factors to muscle dysfunction and mass loss in COPD, a brief description of the epigenetic events and biological targets potentially involved in the final muscle phenotype outcome in models of disuse follows. For instance, in mice, spaceflight and hindlimb suspension resulted in decreased miR-206 levels in the limb muscles of mice, which induce changes in the expression of genes involved in muscle growth and fiber type.86 Nonetheless, prolonged immobilization induced a downregulation of PGC-1alpha and miR-696 in limb muscles of mice.87 In another study, muscle overload induced an upregulation of miR-206, which was associated with slow fiber type formation, which also led to a downregulation of miR-1 and miR133.88 To summarize, a network of microRNAs seems to modulate the expression of MyHC during muscle atrophy and immobilization. However, identification of the specific biological pathways that are targeted by each of the epigenetic events remains to be fully elucidated in skeletal muscles of patients with COPD and in other models in which muscle mass maintenance

and function may be altered, as in immobilization or disuse muscle atrophy models. Evidence of microRNA regulation in muscles of patients with COPD. A significant decrease in the expression of

miR-1 together with a significant rise in HDAC4 protein levels was shown in the vastus lateralis of patients with severe COPD with relatively preserved body composition in a very comprehensive study5 (Table II). Furthermore, expression of the myocardinrelated transcription factors A and B was also shown to be reduced in the limb muscles of the same patients.5 As shown in many previous studies,13,14,22,23 proportions of type I fibers were also significantly reduced in the vastus lateralis of the patients with severe COPD compared with the control subjects.5 The authors concluded that the significant decrease in type I fibers observed in muscles of the severe patients could be attributed to myocardin-related transcription factor/SRF reduced activity levels, which regulate MyHC-I expression,89 and to miR-1 expression levels.5 Additionally, the authors also proposed other biological targets and potential mechanisms in the attempt to explain their study results.5 In this regard, a suggested mechanism was that HDAC4 inhibits MEF2 and SRF activities, which are both important regulators of MyHC-I expression. As mentioned in the previous section, miR-1 also targets IGF-1 expression, whose levels were significantly increased together with protein levels of HDAC4 in the limb muscles of the patients with COPD5 (Table II). Furthermore, the calcineurin pathway,90 which mediates MEF2 activation,91 may also be inhibited by miR-1, thus eventually accounting for the reduced proportions in type I fibers observed in the muscles of the patients.5 Eventually, another likely explanation to account for the rise in HDAC4 levels was that as this enzyme inhibits the expression of follistatin, which antagonizes the action of myostatin, its increased expression may induce

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muscle mass loss.92 Taken together, all these biological mechanisms could partly explain the less fatigueresistant phenotype encountered in the peripheral muscles of patients with severe COPD and muscle atrophy.10,11,13,16,22,23,33,36,38,39,51 In the same study,5 muscle miR-1 expression was also shown to correlate with the amount of type I fibers and with several clinical variables such as smoking history, lung function, body composition, and exercise capacity. Moreover, in the same muscles, the expression of miR-133 and miR-206, whose levels did not differ between patients and healthy control subjects, inversely correlated with daily physical activity among the severe patients.5 YY1 transcription factor may direct HDACs and HTAs to a promoter to activate or repress its function, and it may also inhibit the binding of the transcription activator SRF.93 Muscle regeneration may also be inhibited by YY1 expression through transcriptional silencing of myofibrillar genes.94 Importantly, YY1 activity and expression are also regulated by its localization within the muscle fibers: it becomes active on translocation to the nucleus in response to several stimuli such as depolymerized actin, whereas it remains inactive in the cytoplasm.93 Protein levels of YY1 were assessed in the peripheral muscles of both severe patients with COPD and healthy control subjects in a previous investigation.39 Despite that muscle protein levels did not differ between patients and control subjects, inverse correlations were found between YY1 levels and the size of type I and type IIx fibers, being the latter significantly smaller in the patients.39 Localization of YY1 in the muscle cells, however, differed between patients and healthy control subjects, suggesting that it could be involved in the pathophysiology of the fiber type shift and muscle atrophy events taking place in peripheral muscles of patients with advanced COPD.39 Systemic levels of muscle-enriched microRNAs in 32 COPD. More recently, Donaldson et al elegantly

showed that plasma levels of several muscle-specific microRNAs (miR-1, miR-499, miR-181, miR-133, and miR-206) were increased in patients with severe COPD and relatively well preserved body composition compared with healthy control subjects (Table II). Moreover, despite that several correlations were encountered between plasma microRNA levels and other variables such as lung function and muscle fiber types, microRNA expression did not predict muscle fiber sizes or composition in any of the patients with COPD.32 Epigenetic mechanisms in respiratory and limb muscles of patients with COPD. As mentioned in previous sec-

tions, in COPD, the factors and biological mechanisms leading to muscle dysfunction may differ between respiratory, namely the diaphragm, and lower limb muscles.

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On these grounds, it would be plausible that the epigenetic profile may also vary in muscles of patients with COPD according to body composition, especially that of the lower limbs. In line with this, in our group, we have recently assessed potential differences in the levels of expression of several epigenetic mechanisms in both the diaphragm and vastus lateralis of patients with mildto-moderate COPD with preserved body composition (unpublished observations). Preliminary results from the analyses of this investigation showed that in mildto-moderate patients with COPD, expression levels of several muscle-enriched microRNAs were decreased in the diaphragm, whereas they were increased in the vastus lateralis muscle (unpublished observations, Table II). Moreover, in mild-to-moderate patients with COPD with normal body composition, but not in the control subjects (similar smoking history), the expression of miR-1 was upregulated in the vastus lateralis compared with the diaphragm (Fig 3, A), whereas the expression of miR-133, miR-206, and miR-486 did not differ between respiratory and limb muscles in either patients or control subjects (Fig 3, B, C, and D, respectively). Importantly, the expression of miR-27a and miR-181a was downregulated in the vastus lateralis compared with the diaphragm in both healthy control subjects and patients with COPD (Fig 4, A and B, respectively), whereas the expression of miR-29b was also downregulated in the limb muscle only in the patients (Fig 4, C). Additionally, potential differences in the expression profile of the different microRNAs in each study group were also analyzed in the diaphragm using an analysis of variance test for repeated measures with a Bonferroni’s multiple comparison correction, in which values expressed with the same letter were not statistically different. As such, in the diaphragms of patients with mildto-moderate COPD, miR-133 expression levels were significantly reduced compared with those of miR-1, miR-206, and miR-486, whereas no differences were observed in the expression profile of the same microRNAs in the respiratory muscle of the control subjects (Fig 2, A). Interestingly, expression levels of miR-27a were significantly greater than those of miR29b and miR-181a in the diaphragms of both control subjects and mild-to-moderate patients with COPD (Fig 2, B). Taken together, these findings suggest that differences in the function and activity of the muscle may account for differences in the expression of the different muscle-enriched microRNAs assessed in the study. Future research should focus on the elucidation of the specific targets in the muscles. Furthermore, in another investigation, the vastus lateralis muscle was further analyzed in patients of different degrees of airway obstruction and body

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Fig 3. Mean and standard deviations corresponding to the levels of expression of different muscle-enriched microRNAs (A–D) within the diaphragm and vastus lateralis muscles of healthy nonsmoker control subjects and patients with mild-to-moderate COPD. Parametric unpaired t test was used to explore differences in the levels of expression of the different microRNAs between the respiratory and limb muscle in each study group (control subjects and patients with COPD). The expression of miR-1 was upregulated in the vastus lateralis compared with the diaphragm in the patients with COPD (A), whereas no significant differences were observed in the levels of expression of miR-133, miR-206, and miR-486 between the 2 muscles in either control subjects or patients with COPD (B–D). COPD, chronic obstructive pulmonary disease; miR, microRNA.

Fig 4. Mean and standard deviations corresponding to the levels of expression of different muscle-enriched microRNAs (A–C) within the diaphragm and vastus lateralis muscles of healthy nonsmoker control subjects and patients with moderate-to-severe COPD. Parametric unpaired t test was used to explore differences in the levels of expression of the different microRNAs between the respiratory and limb muscle in each study group (control subjects and patients with COPD). A significant decrease was observed in the levels of expression of miR-27a, miR-29b, and miR-181a in the vastus lateralis compared with the diaphragm in patients with COPD, whereas similar findings were detected in the control subjects, except for miR-29b expression (C). COPD, chronic obstructive pulmonary disease; miR, microRNA.

composition (unpublished observations, Table II). Interestingly, the expression of muscle-enriched microRNAs increased in patients with severe COPD (Table II), whereas it was significantly reduced in the lower limb muscle of patients with severe COPD and cachexia compared with those with identical disease severity but normal body composition (Table II). Preliminary

results of these studies also show that different profiles of expression of muscle-enriched microRNAs were observed when patients were further subdivided in different groups in healthy control subjects and patients with moderate and severe COPD, and in those with concomitant muscle wasting (Fig 5, A and B). Specifically, in the vastus lateralis of patients with severe

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Fig 5. Mean and standard deviations corresponding to the levels of expression of different muscle-enriched microRNAs (A and B) within the vastus lateralis muscle of healthy nonsmoker control subjects and patients with moderate and severe COPD with and without muscle wasting, separately. Significant differences in the levels of the different microRNAs in the muscles of each study group independently were obtained after using an analysis of variance test for repeated measures with a Bonferroni’s multiple comparison correction. Values for each of the microRNA levels within each study group were represented with the same letter. Values with the same letter are not statistically different. COPD, chronic obstructive pulmonary disease; miR, microRNA.

nonwasted COPD and healthy control subjects, miR486 expression levels were shown to be greater among the other analyzed microRNAs (Fig 5, A). Interestingly, expression levels of miR-27a were also significantly greater than those of miR-29b and miR-181a in the lower limb muscle of control subjects and all groups of patients with COPD (Fig 5, B). Eventually, in our group, we have recently evaluated the profile of microRNA expression in the vastus lateralis of patients with very mild COPD and healthy control subjects. Preliminary results have shown that the expression of miR-486 seemed to be greater than that of miR-133 and miR-206 especially in the lower limb muscle of the control subjects (Fig 6, A). Furthermore, miR-27a expression was also higher in the same muscles of the healthy control subjects compared with miR-29b and miR-181a levels, whereas the profile of expression of these microRNAs did not vary in the muscles of the patients with very mild COPD (Fig 6, B).

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As mentioned in a previous section, lysine acetylation has been demonstrated to promote enhanced protein breakdown in several models of muscle wasting through several complex cellular pathways and mechanisms4,5558,95 as also described previously. On the basis of this, it is also likely that muscle wasting in patients with COPD may also be partly mediated by hyperacetylation events of muscle proteins that may stimulate enhanced protein degradation. In keeping with, preliminary results from our group have revealed that total lysine-acetylation protein levels were increased, whereas those of SIRT1 and HDAC3 were reduced in the lower limb muscles of patients with advanced COPD and muscle wasting compared with severe patients without muscle mass loss or the control subjects (unpublished observations). As shown in other muscle wasting conditions,4,95 it is likely that in the muscle-wasted patients with severe COPD, reduced levels of these 2 HDACs and enhanced protein acetylation partly contribute to muscle mass loss and function. Future studies should shed light on the specific biological mechanisms targeted by protein hyperacetylation in skeletal muscles of patients with COPD. In summary, these preliminary descriptive results suggest that a differential epigenetic regulation exists in respiratory and limb muscles of patients with COPD. Moreover, the expression profile of the different muscle-enriched microRNAs also varies in the muscles of the patients depending on the COPD severity and body composition. Future studies should clearly focus on the elucidation of the target biological pathways and mechanisms that may be altered because of modifications in the expression of epigenetic events, namely of muscle-specific microRNAs, in the muscles of patients with COPD. CONCLUSIONS AND FUTURE PERSPECTIVES

To sum up, skeletal muscle dysfunction is a predominant systemic manifestation in patients with COPD, especially in advanced stages of the disease. Several epigenetic mechanisms seem to tightly regulate muscle development and may also be involved in the adaptation of muscles to environmental factors such as immobilization, disuse, deconditioning, or muscle wasting. Several recent studies have shed light on the potential implications of certain epigenetic mechanisms in muscles of patients with COPD and muscle dysfunction. As such, epigenetic mechanisms including musclespecific microRNAs and lysine hyperacetylation seem to play a paramount role in the regulation of muscle mass maintenance in patients with severe COPD. Furthermore, the pattern of expression may also differ between respiratory (diaphragm) and limb muscles

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Fig 6. Mean and standard deviations corresponding to the levels of expression of different muscle-enriched microRNAs (A and B) within the vastus lateralis muscle of healthy nonsmoker control subjects and patients with very mild COPD, separately. Significant differences in the levels of the different microRNA levels in the muscles of each study group independently were obtained after using an analysis of variance test for repeated measures with a Bonferroni’s multiple comparison correction. Values for each of the microRNAs within each study group were represented with the same letter. Values with the same letter are not statistically different. COPD, chronic obstructive pulmonary disease; miR, microRNA.

(vastus lateralis) of patients with COPD of distinct disease severity and body composition. Taken together, the results reported so far point toward the relevance of the epigenetic mechanisms in the regulation of muscle mass maintenance and function. To date, results encountered in the different studies conducted on muscles of patients with COPD have yielded additional questions that will have to be addressed in future investigations. For instance, the effects of high-intensity exercise for several weeks on the epigenetic profile expression of muscles of the lower limbs need to be elucidated in COPD. Another relevant question would be to assess whether epigenetic control may underlie disease progression and susceptibility of patients with COPD to muscle mass and function loss. The role played by the epigenetic mechanisms in the recognized muscle mass loss occurring during the course of exacerbations should also be a matter of research in future investigations. Additionally, further elucidation of the downstream biological pathways and mechanisms specifically targeted by the musclespecific microRNAs in skeletal muscles of patients with COPD would also be of paramount importance for the design of specific therapeutic strategies. Another stimulating avenue for research would be to elucidate the mechanisms whereby lysine hyperacetylation may enhance muscle protein degradation in severe COPD. Finally, identification of the upstream mechanisms and triggers that control the expression of the different epigenetic mechanisms in muscles of patients with COPD also warrants specific attention in future studies.

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Dr Esther Barreiro was a recipient of the ERS COPD Research Award 2008. The authors are very grateful to Ester Puig-Vilanova, MSc, for her help with the statistical analyses and manuscript figures. Author contributions: EB has organized and written the manuscript. JG has contributed to the manuscript writing. Both authors have approved the final version of the manuscript.

REFERENCES

1. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–65. 2. Miravitlles M, Soler-Cataluna JJ, Calle M, et al. Spanish COPD Guidelines (GesEPOC): pharmacological treatment of stable COPD. Spanish Society of Pulmonology and Thoracic Surgery. Arch Bronconeumol 2012;48:247–57. 3. Miravitlles M, Calle M, Soler-Cataluna JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol 2012;48:86–98. 4. Alamdari N, Aversa Z, Castillero E, Hasselgren PO. Acetylation and deacetylation—novel factors in muscle wasting. Metabolism 2013;62:1–11. 5. Lewis A, Riddoch-Contreras J, Natanek SA, et al. Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD. Thorax 2012;67:26–34. 6. Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996;153:976–80. 7. Seymour JM, Spruit MA, Hopkinson NS, et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 2010;36:81–8. 8. Marquis K, Debigare R, Lacasse Y, et al. Midthigh muscle crosssectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:809–13. 9. Swallow EB, Reyes D, Hopkinson NS, et al. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 2007;62:115–20. 10. Levine S, Bashir MH, Clanton TL, Powers SK, Singhal S. COPD elicits remodeling of the diaphragm and vastus lateralis muscles in humans. J Appl Physiol 2013;114:1235–45. 11. Gea J, Agusti A, Roca J. Pathophysiology of muscle dysfunction in COPD. J Appl Physiol 2013;114:1222–34. 12. Mador MJ, Bozkanat E. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Respir Res 2001;2:216–24. 13. Barreiro E, Schols AM, Polkey M, et al. Cytokine profile in quadriceps muscles of patients with severe COPD. Thorax 2008;63:100–7. 14. Fermoselle C, Rabinovich R, Ausin P, et al. Does oxidative stress modulate limb muscle atrophy in severe COPD patients? Eur Respir J 2012;40:851–62.

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Translational Research Volume -, Number -

1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132

Barreiro and Gea

15. Testelmans D, Crul T, Maes K, et al. Atrophy and hypertrophy signalling in the diaphragm of patients with COPD. Eur Respir J 2010;35:549–56. 16. Marin-Corral J, Minguella J, Ramirez-Sarmiento AL, Hussain SN, Gea J, Barreiro E. Oxidised proteins and superoxide anion production in the diaphragm of severe COPD patients. Eur Respir J 2009;33:1309–19. 17. Ottenheijm CA, Heunks LM, Li YP, et al. Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:997–1002. 18. Ottenheijm CA, Lawlor MW, Stienen GJ, Granzier H, Beggs AH. Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy. Hum Mol Genet 2011;20:2015–25. 19. Barreiro E, de la Puente B, Minguella J, et al. Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:1116–24. 20. Barreiro E, Galdiz JB, Marinan M, Alvarez FJ, Hussain SN, Gea J. Respiratory loading intensity and diaphragm oxidative stress: N-acetyl-cysteine effects. J Appl Physiol 2006;100:555–63. 21. Barreiro E, Rabinovich R, Marin-Corral J, Barbera JA, Gea J, Roca J. Chronic endurance exercise induces quadriceps nitrosative stress in patients with severe COPD. Thorax 2009;64:13–9. 22. Barreiro E, Peinado VI, Galdiz JB, et al. Cigarette smoke-induced oxidative stress: a role in chronic obstructive pulmonary disease skeletal muscle dysfunction. Am J Respir Crit Care Med 2010; 182:477–88. 23. Barreiro E, Ferrer D, Sanchez F, et al. Inflammatory cells and apoptosis in respiratory and limb muscles of patients with COPD. J Appl Physiol 2011;111:808–17. 24. Barreiro E, Sznajder JI. Epigenetic regulation of muscle phenotype and adaptation: a potential role in COPD muscle dysfunction. J Appl Physiol 2013;114:1263–72. 25. Casaburi R, Bhasin S, Cosentino L, et al. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:870–8. 26. Coronell C, Orozco-Levi M, Mendez R, Ramirez-Sarmiento A, Galdiz JB, Gea J. Relevance of assessing quadriceps endurance in patients with COPD. Eur Respir J 2004;24:129–36. 27. Creutzberg EC, Wouters EF, Mostert R, Weling-Scheepers CA, Schols AM. Efficacy of nutritional supplementation therapy in depleted patients with chronic obstructive pulmonary disease. Nutrition 2003;19:120–7. 28. Creutzberg EC, Wouters EF, Mostert R, Pluymers RJ, Schols AM. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest 2003;124:1733–42. 29. Crul T, Spruit MA, Gayan-Ramirez G, et al. Markers of inflammation and disuse in vastus lateralis of chronic obstructive pulmonary disease patients. Eur J Clin Invest 2007;37:897–904. 30. Crul T, Testelmans D, Spruit MA, et al. Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD. Cell Physiol Biochem 2010;25:491–500. 31. Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153(6 Pt 1): 1958–64. 32. Donaldson A, Natanek SA, Lewis A, et al. Increased skeletal muscle-specific microRNA in the blood of patients with COPD. Thorax 2013;68:1140–9. 33. Doucet M, Russell AP, Leger B, et al. Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:261–9.

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34. Fermoselle C, Sanchez F, Barreiro E. Reduction of muscle mass mediated by myostatin in an experimental model of pulmonary emphysema. Arch Bronconeumol 2011;47:590–8. 35. Gayan-Ramirez G, Decramer M. Mechanisms of striated muscle dysfunction during acute exacerbations of COPD. J Appl Physiol 2013;114:1291–9. 36. Gosker HR, Zeegers MP, Wouters EF, Schols AM. Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta-analysis. Thorax 2007;62:944–9. 37. Laviolette L, Lands LC, Dauletbaev N, et al. Combined effect of dietary supplementation with pressurized whey and exercise training in chronic obstructive pulmonary disease: a randomized, controlled, double-blind pilot study. J Med Food 2010;13:589–98. 38. Montes de Oca M, Celli BR. Peripheral muscles in COPD: deconditioning or myopathy? Arch Bronconeumol 2001;37:82–7. 39. Natanek SA, Riddoch-Contreras J, Marsh GS, et al. Yin Yang 1 expression and localisation in quadriceps muscle in COPD. Arch Bronconeumol 2011;47:296–302. 40. Puente-Maestu L, Perez-Parra J, Godoy R, et al. Abnormal transition pore kinetics and cytochrome C release in muscle mitochondria of patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2009;40:746–50. 41. Puente-Maestu L, Perez-Parra J, Godoy R, et al. Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur Respir J 2009;33:1045–52. 42. Puente-Maestu L, Lazaro A, Tejedor A, et al. Effects of exercise on mitochondrial DNA content in skeletal muscle of patients with COPD. Thorax 2011;66:121–7. 43. Puente-Maestu L, Tejedor A, Lazaro A, et al. Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease and its relationship with exercise oxidative stress. Am J Respir Cell Mol Biol 2012;47: 358–62. 44. Puente-Maestu L, Lazaro A, Humanes B. Metabolic derangements in COPD muscle dysfunction. J Appl Physiol 2013;114:1282–90. 45. Rodriguez DA, Kalko S, Puig-Vilanova E, et al. Muscle and blood redox status after exercise training in severe COPD patients. Free Radic Biol Med 2012;52:88–94. 46. Swallow EB, Gosker HR, Ward KA, et al. A novel technique for nonvolitional assessment of quadriceps muscle endurance in humans. J Appl Physiol 2007;103:739–46. 47. Vogiatzis I, Terzis G, Nanas S, et al. Skeletal muscle adaptations to interval training in patients with advanced COPD. Chest 2005; 128:3838–45. 48. Vogiatzis I, Stratakos G, Simoes DC, et al. Effects of rehabilitative exercise on peripheral muscle TNFalpha, IL-6, IGF-I and MyoD expression in patients with COPD. Thorax 2007;62:950–6. 49. Vogiatzis I, Simoes DC, Stratakos G, et al. Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD. Eur Respir J 2010;36:301–10. 50. Vogiatzis I, Terzis G, Stratakos G, et al. Effect of pulmonary rehabilitation on peripheral muscle fiber remodeling in patients with COPD in GOLD stages II to IV. Chest 2011;140:744–52. 51. Whittom F, Jobin J, Simard PM, et al. Histochemical and morphological characteristics of the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Med Sci Sports Exerc 1998;30:1467–74. 52. Baar K. Epigenetic control of skeletal muscle fibre type. Acta Physiol (Oxf) 2010;199:477–87. 53. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31:27–36. 54. Lawless MW, O’Byrne KJ, Gray SG. Targeting oxidative stress in cancer. Expert Opin Ther Targets 2010;14:1225–45.

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Barreiro and Gea

55. Chen LF, Greene WC. Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation. J Mol Med (Berl) 2003;81:549–57. 56. Sadoul K, Boyault C, Pabion M, Khochbin S. Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 2008;90:306–12. 57. Seigneurin-Berny D, Verdel A, Curtet S, et al. Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol Cell Biol 2001;21:8035–44. 58. Scroggins BT, Robzyk K, Wang D, et al. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell 2007;25:151–9. 59. Jacobs SA, Khorasanizadeh S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 2002; 295:2080–3. 60. Taverna SD, Ilin S, Rogers RS, et al. Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs. Mol Cell 2006;24: 785–96. 61. Cote J, Richard S. Tudor domains bind symmetrical dimethylated arginines. J Biol Chem 2005;280:28476–83. 62. Huang Y, Fang J, Bedford MT, Zhang Y, Xu RM. Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 2006;312:748–51. 63. Angulo M, Lecuona E, Sznajder JI. Role of MicroRNAs in lung disease. Arch Bronconeumol 2012;48:325–30. 64. Lee Y, Kim M, Han J, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004;23:4051–60. 65. Perdiguero E, Sousa-Victor P, Ballestar E, Munoz-Canoves P. Epigenetic regulation of myogenesis. Epigenetics 2009;4:541–50. 66. Kurihara Y, Watanabe Y. Arabidopsis micro-RNA biogenesis through Dicer-like 1 protein functions. Proc Natl Acad Sci U S A 2004;101:12753–8. 67. Hutvagner G. Small RNA asymmetry in RNAi: function in RISC assembly and gene regulation. FEBS Lett 2005;579:5850–7. 68. O’Rourke JR, Georges SA, Seay HR, et al. Essential role for Dicer during skeletal muscle development. Dev Biol 2007;311:359–68. 69. Deato MD, Marr MT, Sottero T, Inouye C, Hu P, Tjian R. MyoD targets TAF3/TRF3 to activate myogenin transcription. Mol Cell 2008;32:96–105. 70. Nakajima N, Takahashi T, Kitamura R, et al. MicroRNA-1 facilitates skeletal myogenic differentiation without affecting osteoblastic and adipogenic differentiation. Biochem Biophys Res Commun 2006;350:1006–12. 71. Lucarelli M, Fuso A, Strom R, Scarpa S. The dynamics of myogenin site-specific demethylation is strongly correlated with its expression and with muscle differentiation. J Biol Chem 2001; 276:7500–6. 72. Palacios D, Puri PL. The epigenetic network regulating muscle development and regeneration. J Cell Physiol 2006;207:1–11. 73. Guenther MG, Levine SS, Boyer LA, Jaenisch R, Young RA. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 2007;130:77–88. 74. Kuang S, Kuroda K, Le GF, Rudnicki MA. Asymmetric selfrenewal and commitment of satellite stem cells in muscle. Cell 2007;129:999–1010. 75. McKinnell IW, Ishibashi J, Le GF, et al. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nat Cell Biol 2008;10:77–84. 76. Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 2006;38:228–33.

77. Elia L, Contu R, Quintavalle M, et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 2009;120:2377–85. 78. Anderson C, Catoe H, Werner R. MIR-206 regulates connexin43 expression during skeletal muscle development. Nucleic Acids Res 2006;34:5863–71. 79. Dey BK, Gagan J, Dutta A. miR-206 and -486 induce myoblast differentiation by downregulating Pax7. Mol Cell Biol 2011;31: 203–14. 80. Crist CG, Montarras D, Pallafacchina G, et al. Muscle stem cell behavior is modified by microRNA-27 regulation of Pax3 expression. Proc Natl Acad Sci U S A 2009;106:13383–7. 81. Naguibneva I, Ameyar-Zazoua M, et al. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nat Cell Biol 2006;8:278–84. Q16 82. Wang H, Garzon R, Sun H, et al. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 2008;14:369–81. 83. Wang L, Zhou L, Jiang P, et al. Loss of miR-29 in myoblasts contributes to dystrophic muscle pathogenesis. Mol Ther 2012;20: 1222–33. 84. Rao PK, Kumar RM, Farkhondeh M, Baskerville S, Lodish HF. Myogenic factors that regulate expression of muscle-specific microRNAs. Proc Natl Acad Sci U S A 2006;103:8721–6. 85. Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 2005;436:214–20. 86. Allen DL, Bandstra ER, Harrison BC, et al. Effects of spaceflight on murine skeletal muscle gene expression. J Appl Physiol 2009; 106:582–95. 87. Aoi W, Naito Y, Mizushima K, et al. The microRNA miR-696 regulates PGC-1{alpha} in mouse skeletal muscle in response to physical activity. Am J Physiol Endocrinol Metab 2010;298: E799–806. 88. McCarthy JJ, Esser KA. MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy. J Appl Physiol 2007;102:306–13. 89. Allen DL, Weber JN, Sycuro LK, Leinwand LA. Myocyte enhancer factor-2 and serum response factor binding elements regulate fast myosin heavy chain transcription in vivo. J Biol Chem 2005;280:17126–34. 90. Ikeda S, He A, Kong SW, et al. MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Mol Cell Biol 2009;29:2193–204. 91. Wu H, Rothermel B, Kanatous S, et al. Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. EMBO J 2001;20:6414–23. 92. Sun Y, Ge Y, Drnevich J, Chen J. Mammalian target of rapamycin regulates miRNA-1 and follistatin in skeletal myogenesis. J Cell Biol 2010;189:1157–69. 93. Ellis PD, Martin KM, Rickman C, Metcalfe JC, Kemp PR. Increased actin polymerization reduces the inhibition of serum response factor activity by Yin Yang 1. Biochem J 2002;364(Pt 2):547–54. 94. Wang H, Hertlein E, Bakkar N, et al. NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Mol Cell Biol 2007;27: 4374–87. 95. Alamdari N, Smith IJ, Aversa Z, Hasselgren PO. Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2010;299:R509–20.

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Epigenetics and muscle dysfunction in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease and a major leading cause of morbidity and mortality worl...
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