Genome-wide mRNA expression profiling in vastus lateralis of COPD patients with low and normal fat free mass index and healthy controls

Respiratory Research

William MacNee²  Ricardo Bastos³  Ramzi Lakhdar²  MaCarmen Díaz-Ramos¹  Donald R Dunbar⁴  Jonathan R Manning⁴  Ellen Drost²  Roberto A Rabinovich² 

[1] Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK;Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain;Centre for Cardiovascular Science, University of Edinburgh, Scotland, UK

关键词: Ageing;    Gene expression;    Skeletal muscle wasting;    Skeletal Muscle Dysfunction;    COPD;   

Others  :  1137197
DOI  :  10.1186/s12931-014-0139-5

 received in 2014-05-12, accepted in 2014-10-24,  发布年份 2015

【 摘 要 】

Background

Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD.

Methods

We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPD_L) (FEV₁ 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m⁻²) with patients with COPD and normal FFMI (COPD_N) (FEV₁ 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m⁻²) and a group of age and sex matched healthy controls (C) (FEV₁ 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m⁻²) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting.

Results

A subset of 42 genes was differentially expressed in COPD_L in comparison to both COPD_N and C (PFP < 0.05; −1.5 ≥ FC ≥ 1.5). The altered expression of several of these genes was confirmed by real time TaqMan PCR and correlated with different functional and structural muscle parameters. Five of these genes (CDKN1A, GADD45A, PMP22, BEX2, CGREF1, CYR61), were associated with cell cycle arrest and growth regulation and had been previously identified in studies relating muscle wasting and ageing. Protein levels of CDKN1A, a recognized marker of premature ageing/cell cycle arrest, were also found to be increased in COPD_L.

Conclusions

This study provides evidence of differentially expressed genes in peripheral muscle in COPD patients corresponding to relevant biological processes associated with skeletal muscle wasting and provides potential targets for future therapeutic interventions to prevent loss of muscle function and mass in COPD.

【 授权许可】

   
2015 Rabinovich et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Agusti AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X: Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 2003, 21:347-360.
• [2]Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare R, Dekhuijzen PN, Franssen F, Gayan-Ramirez G, Gea J, Gosker HR, Gosselink R, Hayot M, Hussain SN, Janssens W, Polkey MI, Roca J, Saey D, Schols AM, Spruit MA, Steiner M, Taivassalo T, Troosters T, Vogiatzis I, Wagner PD: An official american thoracic society/european respiratory society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014, 189:e15-e62.
• [3]Decramer M, Gosselink R, Troosters T, Schepers R: Peripheral muscle weakness is associated with reduced survival in COPD. Am J Respir Crit Care Med 1998, 157:A19.
• [4]Engelen MPKJ, Schols AMWJ, Does JD, Wouters EFM: Skeletal muscle weakness is associated with wasting of extremity fat-free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 2000, 71:733-738.
• [5]Bernard S, Leblanc P, Whittom F, Carrier G, Jobin J, Belleau R, Maltais F: Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998, 158:629-634.
• [6]Vilaro J, Rabinovich R, Gonzalez-deSuso JM, Troosters T, Rodriguez D, Barbera JA, Roca J: Clinical assessment of peripheral muscle function in patients with chronic obstructive pulmonary disease. Am J Phys Med Rehabil 2009, 88:39-46.
• [7]Schols AMWJ, Soeters PB, Dingemans AMC, Mostert R, Frantzen PJ, Wouters EFM: Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993, 147:1151-1156.
• [8]Baarends EM, Schols AM, Mostert R, Wouters EF: Peak exercise response in relation to tissue depletion in patients with chronic obstructive pulmonary disease. Eur Respir J 1997, 10:2807-2813.
• [9]Kobayashi A, Yoneda T, Yoshikawa M, Ikuno M, Takenaka H, Fukuoka A, Narita N, Nezu K: The relation of fat-free mass to maximum exercise performance in patients with chronic obstructive pulmonary disease. Lung 2000, 178:119-127.
• [10]Schols AM, Mostert R, Soeters PB, Wouters EF: Body composition and exercise performance in patients with chronic obstructive pulmonary disease. Thorax 1991, 46:695-699.
• [11]Mostert R, Goris A, Weling-Scheepers C, Wouters EF, Schols AM: Tissue depletion and health related quality of life in patients with chronic obstructive pulmonary disease. Respir Med 2000, 94:859-867.
• [12]Marquis K, Debigare R, Lacasse Y, Leblanc P, Jobin J, Carrier G, Maltais F: Midthigh muscle cross-sectional 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, 166:809-813.
• [13]Mador MJ: Muscle mass, not body weight, predicts outcome in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002, 166:787-789.
• [14]Engelen MPKJ, Schols AMWJ, Baken WC, Wesseling GJ, Wouters EFM: Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994, 7:1793-1797.
• [15]Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ: Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001, 164:1414-1418.
• [16]Jakobsson P, Jorfeldt L, Brundin A: Skeletal muscle metabolits and fibre types in patients with advanced chronic obstructive pulmonary disease (COPD), with and without chronic respiratory failure. Eur Respir J 1990, 3:192-196.
• [17]Simard C, Maltais F, Leblanc P, Simard P, Jobin J: Mitochondrial and capillarity changes in vastus lateralis muscle of COPD patients: electron microscopy study. Med Sci Sports Exerc 1996, 28:S95.
• [18]Rabinovich RA, Bastos R, Ardite E, Orozco-Levi M, Gea J, Vilar¢ J, Barber… JA, Rodriguez-Roisin R, Fernandez-Checa JC, Roca J: Mitochondrial dysfunction in COPD patients with low body mass index. Eur Respir J 2007, 29:643-650.
• [19]Puente-Maestu L, Perez-Parra J, Godoy R, Moreno N, Tejedor A, Gonzalez-Aragoneses F, Bravo JL, Alvarez FV, Camano S, Agusti A: Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur Respir J 2009, 33:1045-1052.
• [20]Ito K, Mercado N. STOP accelerating lung aging for the treatment of COPD. Exp Gerontol. 2014;http://dx.doi.org/10.1016/j.exger.2014.03.014.
• [21]Theriault ME, Pare ME, Maltais F, Debigare R: Satellite cells senescence in limb muscle of severe patients with COPD. PloS One 2012, 7:e39124.
• [22]Bernard S, Whittom F, Leblanc P, Jobin J, Belleau R, Berube C, Carrier G, Maltais F: Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999, 159:896-901.
• [23]Decramer M. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (updated 2014). 2014;http://www.goldcopd.com.
• [24]ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories: ATS statement: guidelines for the six-minute walk test Am J Respir Crit Care Med 2002, 166:111-117.
• [25]Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, Bouillon R, Decramer M: Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax 2003, 58:752-756.
• [26]Jones PW, Quirk FH, Baveystock CM, Littlejohns P: A self-complete measure of health status for chronic airflow limitation. Am Rev Respir Dis 1992, 145:1321-1327.
• [27]Voorrips LE, Ravelli AC, Dongelmans PC, Deurenberg P, Van Staveren WA: A physical activity questionnaire for the elderly. Med Sci Sports Exerc 1991, 23:974-979.
• [28]Garrod R, Bestall JC, Paul EA, Wedzicha JA, Jones PW: Development and validation of a standardized measure of activity of daily living in patients with severe COPD: the London chest activity of daily living scale (LCADL). Respir Med 2000, 94:589-596.
• [29]Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF: Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr 2005, 82:53-59.
• [30]Toth ZE, Mezey E: Simultaneous visualization of multiple antigens with tyramide signal amplification using antibodies from the same species. J Histochem Cytochem 2007, 55:545-554.
• [31]Team RDC: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing In Book A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria; 2005.
• [32]Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J: Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004, 5:R80. BioMed Central Full Text
• [33]Breitling R, Armengaud P, Amtmann A, Herzyk P: Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett 2004, 573:83-92.
• [34]Hong F, Breitling R, McEntee CW, Wittner BS, Nemhauser JL, Chory J: RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis. Bioinformatics 2006, 22:2825-2827.
• [35]Gallagher IJ, Scheele C, Keller P, Nielsen AR, Remenyi J, Fischer CP, Roder K, Babraj J, Wahlestedt C, Hutvagner G, Pedersen BK, Timmons JA: Integration of microrna changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes. Genome Med 2010, 2:9. BioMed Central Full Text
• [36]Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, Miller-Graziano C, Moldawer LL, Mindrinos MN, Davis RW, Tompkins RG, Lowry SF: A network-based analysis of systemic inflammation in humans. Nature 2005, 437:1032-1037.
• [37]Doucet M, Russell AP, Leger B, Debigare R, Joanisse DR, Caron MA, Leblanc P, Maltais F: Muscle atrophy and hypertrophy signaling in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007, 176:261-269.
• [38]Dong C, Li Q, Lyu SC, Krensky AM, Clayberger C: A novel apoptosis pathway activated by the carboxyl terminus of p21. Blood 2005, 105:1187-1194.
• [39]Ebert SM, Dyle MC, Kunkel SD, Bullard SA, Bongers KS, Fox DK, Dierdorff JM, Foster ED, Adams CM: Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. J Biol Chem 2012, 287:27290-27301.
• [40]Caiozzo VJ, Utkan A, Chou R, Khalafi A, Chandra H, Baker M, et al. Effects of distraction on muscle length: mechanisms involved in sarcomerogenesis. Clin Orthop Relat Res 2002:S133-145
• [41]Bongers KS, Fox DK, Ebert SM, Kunkel SD, Dyle MC, Bullard SA, Dierdorff JM, Adams CM: Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4. Am J Physiol Endocrinol Metab 2013, 305:E907-E915.
• [42]Calura E, Cagnin S, Raffaello A, Laveder P, Lanfranchi G, Romualdi C: Meta-analysis of expression signatures of muscle atrophy: gene interaction networks in early and late stages. BMC Genomics 2008, 9:630. BioMed Central Full Text
• [43]De Aguilar JL G, Niederhauser-Wiederkehr C, Halter B, De Tapia M, Di Scala F, Demougin P, Dupuis L, Primig M, Meininger V, Loeffler JP: Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Physiol Genomics 2008, 32:207-218.
• [44]Ohsawa Y, Hagiwara H, Nakatani M, Yasue A, Moriyama K, Murakami T, Tsuchida K, Noji S, Sunada Y: Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition. J Clin Invest 2006, 116:2924-2934.
• [45]Thomas M, Langley B, Berry C, Sharma M, Kirk S, Bass J, Kambadur R: Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem 2000, 275:40235-40243.
• [46]Dotto GP: p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta 2000, 1471:M43-M56.
• [47]Gartel AL, Tyner AL: The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 2002, 1:639-649.
• [48]Wang A, Gu J, Judson-Kremer K, Powell KL, Mistry H, Simhambhatla P, Aldaz CM, Gaddis S, MacLeod MC: Response of human mammary epithelial cells to DNA damage induced by BPDE: involvement of novel regulatory pathways. Carcinogenesis 2003, 24:225-234.
• [49]Okamoto Y, Chaves A, Chen J, Kelley R, Jones K, Weed HG, Gardner KL, Gangi L, Yamaguchi M, Klomkleaw W, Nakayama T, Hamlin RL, Carnes C, Altschuld R, Bauer J, Hai T: Transgenic mice with cardiac-specific expression of activating transcription factor 3, a stress-inducible gene, have conduction abnormalities and contractile dysfunction. Am J Pathol 2001, 159:639-650.
• [50]Laure L, Suel L, Roudaut C, Bourg N, Ouali A, Bartoli M, Richard I, Daniele N: Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling. FEBS J 2009, 276:669-684.
• [51]Wu CL, Kandarian SC, Jackman RW: Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3. PloS One 2011, 6:e16171.
• [52]Timchenko NA, Wilde M, Nakanishi M, Smith JR, Darlington GJ: CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev 1996, 10:804-815.
• [53]Timchenko NA, Harris TE, Wilde M, Bilyeu TA, Burgess-Beusse BL, Finegold MJ, Darlington GJ: CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice. Mol Cell Biol 1997, 17:7353-7361.
• [54]Agusti AG, Sauleda J, Miralles C, Gomez C, Togores B, Sala E, Batle S, Busquets X: Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002, 166:485-489.
• [55]Barreiro E, Ferrer D, Sanchez F, Minguella J, Marin-Corral J, Martinez-Llorens J, Lloreta J, Gea J: Inflammatory cells and apoptosis in respiratory and limb muscles of patients with COPD. J Appl Physiol 2011, 111:808-817.
• [56]Gosker HR, Kubat B, Schaart G, van der Vusse GJ, Wouters EF, Schols AM: Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease. Eur Respir J 2003, 22:280-285.
• [57]Suzuki A, Tsutomi Y, Akahane K, Araki T, Miura M: Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene 1998, 17:931-939.
• [58]Hubal MJ, Chen TC, Thompson PD, Clarkson PM: Inflammatory gene changes associated with the repeated-bout effect. Am J Physiol Regul Integr Comp Physiol 2008, 294:R1628-R1637.
• [59]Kivela R, Kyrolainen H, Selanne H, Komi PV, Kainulainen H, Vihko V: A single bout of exercise with high mechanical loading induces the expression of Cyr61/CCN1 and CTGF/CCN2 in human skeletal muscle. J Appl Physiol (1985) 2007, 103:1395-1401.
• [60]Kivela R, Silvennoinen M, Lehti M, Jalava S, Vihko V, Kainulainen H: Exercise-induced expression of angiogenic growth factors in skeletal muscle and in capillaries of healthy and diabetic mice. Cardiovasc Diabetol 2008, 7:13. BioMed Central Full Text
• [61]O’Connor RS, Mills ST, Jones KA, Ho SN, Pavlath GK: A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis. J Cell Sci 2007, 120:149-159.
• [62]Rayssac A, Neveu C, Pucelle M, Van den Berghe L, Prado-Lourenco L, Arnal JF, Chaufour X, Prats AC: IRES-based vector coexpressing FGF2 and Cyr61 provides synergistic and safe therapeutics of lower limb ischemia. Mol Ther 2009, 17:2010-2019.
• [63]Lehnert SA, Byrne KA, Reverter A, Nattrass GS, Greenwood PL, Wang YH, Hudson NJ, Harper GS: Gene expression profiling of bovine skeletal muscle in response to and during recovery from chronic and severe undernutrition. J Anim Sci 2006, 84:3239-3250.
• [64]Magnusson C, Svensson A, Christerson U, Tagerud S: Denervation-induced alterations in gene expression in mouse skeletal muscle. Eur J Neurosci 2005, 21:577-580.
• [65]Lobel M, Bauer S, Meisel C, Eisenreich A, Kudernatsch R, Tank J, Rauch U, Kuhl U, Schultheiss HP, Volk HD, Poller W, Scheibenbogen C: Ccn1: a novel inflammation-regulated biphasic immune cell migration modulator. Cellular and molecular life sciences : CMLS 2012, 69:3101-3113.
• [66]Fermoselle C, Rabinovich R, Ausin P, Puig-Vilanova E, Coronell C, Sanchez F, Roca J, Gea J, Barreiro E: Does oxidative stress modulate limb muscle atrophy in severe COPD patients? Eur Respir J 2012, 40:851-862.
• [67]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, 64:13-19.
• [68]Rabinovich RA, Ardite E, Troosters T, Carb¢ N, Alonso J, de Suso JM G, Vilar¢ J, Barber… JA, Figueras M, Argiles JM, Fernandez Checa JC, Roca J: Reduced muscle redox capacity after endurance training in copd patients. American Journal of Respiratory and Critical Care Medicine 2001, 164:1114-1118.
• [69]Rabinovich RA, Ardite E, Mayer AM, Figueras Polo M, Vilar¢ J, Argiles JM, Roca J: Training depletes muscle glutathione in COPD patients with low body mass index. Respiration 2006, 73:757-761.
• [70]Paine A, Eiz-Vesper B, Blasczyk R, Immenschuh S: Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 2010, 80:1895-1903.
• [71]Rabinovich RA, Figueras M, Ardite E, Carbo N, Troosters T, Filella X, Barbera JA, Fernandez-Checa JC, Argiles JM, Roca J: Increased tumour necrosis factor-alpha plasma levels during moderate-intensity exercise in COPD patients. Eur Respir J 2003, 21:789-794.
• [72]Montes De Oca M, Torres SH, De Sanctis J, Mata A, Hernandez N, Talamo C: Skeletal muscle inflammation and nitric oxide in patients with COPD. Eur Respir J 2005, 26:390-397.
• [73]Remels AH, Gosker HR, Schrauwen P, Hommelberg PP, Sliwinski P, Polkey M, Galdiz J, Wouters EF, Langen RC, Schols AM: TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia? FASEB J 2010, 24:5052-5062.
• [74]Agusti A, Morla M, Sauleda J, Saus C, Busquets X: NF-kappaB activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight. Thorax 2004, 59:483-487.
• [75]Plant PJ, Brooks D, Faughnan M, Bayley T, Bain J, Singer L, Correa J, Pearce D, Binnie M, Batt J: Cellular markers of muscle atrophy in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2010, 42:461-471.
• [76]Vogiatzis I, Simoes DC, Stratakos G, Kourepini E, Terzis G, Manta P, Athanasopoulos D, Roussos C, Wagner PD, Zakynthinos S: Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD. Eur Respir J 2010, 36:301-310.
• [77]Dogra C, Changotra H, Wedhas N, Qin X, Wergedal JE, Kumar A: TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. FASEB J 2007, 21:1857-1869.
• [78]Mittal A, Bhatnagar S, Kumar A, Lach-Trifilieff E, Wauters S, Li H, Makonchuk DY, Glass DJ: The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J Cell Biol 2010, 188:833-849.
• [79]Park CY, Pierce SA, Von Drehle M, Ivey KN, Morgan JA, Blau HM, Srivastava D: skNAC, a Smyd1-interacting transcription factor, is involved in cardiac development and skeletal muscle growth and regeneration. Proc Natl Acad Sci U S A 2010, 107:20750-20755.
• [80]Wu Z, Nagano I, Takahashi Y: Candidate genes responsible for common and different pathology of infected muscle tissues between Trichinella spiralis and T. pseudospiralis infection. Parasitol Int 2008, 57:368-378.
• [81]Crul T, Spruit MA, Gayan-Ramirez G, Quarck R, Gosselink R, Troosters T, Pitta F, Decramer M: Markers of inflammation and disuse in vastus lateralis of chronic obstructive pulmonary disease patients. Eur J Clin Invest 2007, 37:897-904.
• [82]Theriault ME, Pare ME, Lemire BB, Maltais F, Debigare R: Regenerative defect in vastus lateralis muscle of patients with chronic obstructive pulmonary disease. Respir Res 2014, 15:35. BioMed Central Full Text
• [83]Fredriksson K, Tjader I, Keller P, Petrovic N, Ahlman B, Scheele C, Wernerman J, Timmons JA, Rooyackers O: Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure. PloS One 2008, 3:e3686.
• [84]Stephens NA, Gallagher IJ, Rooyackers O, Skipworth RJ, Tan BH, Marstrand T, Ross JA, Guttridge DC, Lundell L, Fearon KC, Timmons JA: Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med 2010, 2:1. BioMed Central Full Text
• [85]Welle S, Brooks AI, Delehanty JM, Needler N, Bhatt K, Shah B, Thornton CA: Skeletal muscle gene expression profiles in 20–29 year old and 65–71 year old women. Exp Gerontol 2004, 39:369-377.
• [86]Melov S, Tarnopolsky MA, Beckman K, Felkey K, Hubbard A: Resistance exercise reverses aging in human skeletal muscle. PloS One 2007, 2:e465.
• [87]Keller P, Vollaard NB, Gustafsson T, Gallagher IJ, Sundberg CJ, Rankinen T, Britton SL, Bouchard C, Koch LG, Timmons JA: A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype. J Appl Physiol 2011, 110:46-59.
• [88]Debigare R, Maltais F, Cote CH, Michaud A, Caron MA, Mofarrahi M, Leblanc P, Hussain SN: Profiling of mRNA expression in quadriceps of patients with COPD and muscle wasting. Copd 2008, 5:75-84.
• [89]Crul T, Testelmans D, Spruit MA, Troosters T, Gosselink R, Geeraerts I, Decramer M, Gayan-Ramirez G: Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD. Cell Physiol Biochem 2010, 25:491-500.
• [90]Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997, 390:45-51.
• [91]Kim JS, Kim EJ, Kim HJ, Yang JY, Hwang GS, Kim CW: Proteomic and metabolomic analysis of H2O2-induced premature senescent human mesenchymal stem cells. Exp Gerontol 2011, 46:500-510.
• [92]Janssen I, Heymsfield SB, Ross R: Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 2002, 50:889-896.
• [93]Schols AM, Wouters EF, Soeters PB, Westerterp KR: Body composition by bioelectrical-impedance analysis compared with deuterium dilution and skinfold anthropometry in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 1991, 53:421-424.
• [94]Bosaeus I, Wilcox G, Rothenberg E, Strauss BJ: Skeletal muscle mass in hospitalized elderly patients: Comparison of measurements by single-frequency BIA and DXA. Clin Nutr 2014, 33:426-431.
• [95]Seymour JM, Ward K, Sidhu PS, Puthucheary Z, Steier J, Jolley CJ, Rafferty G, Polkey MI, Moxham J: Ultrasound measurement of rectus femoris cross-sectional area and the relationship with quadriceps strength in COPD. Thorax 2009, 64:418-423.
• [96]Franssen FM, Broekhuizen R, Janssen PP, Wouters EF, Schols AM: Effects of whole-body exercise training on body composition and functional capacity in normal-weight patients with COPD. Chest 2004, 125:2021-2028.
• [97]Slinde F, Gronberg A, Engstrom CP, Rossander-Hulthen L, Larsson S: Body composition by bioelectrical impedance predicts mortality in chronic obstructive pulmonary disease patients. Respir Med 2005, 99:1004-1009.
• [98]Thibault R, Le Gallic E, Picard-Kossovsky M, Darmaun D, Chambellan A: [Assessment of nutritional status and body composition in patients with COPD: comparison of several methods]. Rev Mal Respir 2010, 27:693-702.
• [99]Montes De Oca M, Loeb E, Torres SH, De Sanctis J, Hernandez N, Talamo C: Peripheral muscle alterations in non-COPD smokers. Chest 2008, 133:13-18.
• [100]Doll R, Peto R, Boreham J, Sutherland I: Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004, 328:1519.