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ORIGINAL ARTICLE
Irisin, a newly discovered myokine, is a novel biomarker associated with physical activity in patients with chronic obstructive pulmonary disease NAOKI IJIRI, HIROSHI KANAZAWA, KAZUHISA ASAI, TETSUYA WATANABE AND KAZUTO HIRATA Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
ABSTRACT Background and objective: Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise. Physical activity has been emphasized as one of the principal targets of the treatment for chronic obstructive pulmonary disease (COPD). This study was designed to evaluate the possibility of using serum irisin level as a novel biomarker associated with physical activity in patients with COPD. Methods: We measured the serum irisin level in 72 COPD patients and 27 control subjects, and investigated its correlation to pulmonary function parameters, exercise capacity and physical activity level. In addition, we analysed the effects of acute and chronic exercise on serum irisin level. Results: Fat-free mass index was not significantly different between the two study groups. However, lower serum irisin level was observed in COPD patients than in the control subjects (COPD patients: median (interquartile range) 31.6 (22.7–40.4) ng/mL; control subjects: 50.7 (39.3–65.8) ng/mL; P < 0.001). The serum irisin level did not significantly correlate with any pulmonary function parameters and 6-min walk distance. However, serum irisin level was associated with the physical activity level in all subjects. In COPD patients, acute exercise did not affect serum irisin level, but an 8-week exercise training was linked to the significant increase in its level. Conclusions: Circulating irisin could be used to evaluate physical activity in COPD patients and increased after an 8-week exercise training. Serum irisin level may prove to be a valuable biomarker in clinical follow up of COPD. Correspondence: Hiroshi Kanazawa, Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Email: [email protected] Received 18 September 2014; invited to revise 25 November and 23 December 2014; revised 10 and 25 December 2014; accepted 12 January 2015 (Associate Editor: Melissa Benton). Article first published online: 20 March 2015 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
SUMMARY AT A GLANCE Serum levels of irisin increased in COPD patients following an 8-week training programme. Serum irisin level could be used as a novel biomarker associated with physical activity in patients with COPD and may prove to be a valuable tool in clinical follow up of COPD.
Key words: 6-min walk distance, exercise, fibronectin type III domain-containing protein 5, irisin, physical activity. Abbreviations: 6MWD, 6-min walk distance; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity of the lung for carbon monoxide; ELISA, enzyme-linked immunosorbent assay; FFMI, fat-free mass index; FNDC5, fibronectin type III domaincontaining protein 5; WBV, whole body vibration.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible, usually progressive and associated with an abnormal inflammatory response of the lung.1 It has been widely recognized to include a variety of extrapulmonary complications that may contribute to its severity.2 For example, patients with COPD often experience weight loss associated with muscle atrophy, which is thought to have adverse effects on physical activity and to be one of the independent risk factors for mortality.3 The patients frequently complain of dyspnoea related to various routine tasks and may find themselves in a downward spiral of symptom-related inactivity, leading to deconditioning and muscle weakness.4,5 Physical activity is an important clinical parameter in many chronic diseases including COPD.6 Limited physical activity has been associated with more frequent hospitalization caused by exacerbations in COPD; furthermore, physical activity level has been shown to predict mortality in these patients.7 The physical activity reported by individual patients has
© 2015 The Authors Respirology (2015) 20, 612–617 Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology doi: 10.1111/resp.12513
613
Circulating irisin in COPD
been recognized as one of the principal targets of treatment for COPD.8 Thus, quantifying physical activity in daily life, together with its intensity and frequency, is of great value. To date, physical activity can be evaluated by self-report questionnaires, as well as by using motion sensors.9–12 Because the daily average of these data in individual patients is not simple to evaluate, a specific and stable biomarker of physical activity in patients with COPD is required for wide use in clinical follow up of the disease. Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise.13–15 It is regulated by peroxisome proliferator-activated receptor-γ coactivator-1-α and is proteolytically processed from the product of the fibronectin type III domaincontaining protein 5 (FNDC5) gene prior to being released into the circulation.16,17 Thus, irisin could be a rational biomarker for diseases linked with physical inactivity.18,19 Therefore, the present study was designed to compare serum irisin levels between patients with COPD and control subjects, and investigate the correlations to pulmonary function parameters, exercise capacity and physical activity in COPD patients. In addition, we analysed the effects of acute and chronic exercise on serum irisin level in affected patients.
METHODS Study subjects Seventy-two patients with COPD and 27 control subjects were recruited into the study. All COPD patients were former smokers having a previous smoking history >20 pack-years, and all control subjects were never-smokers. COPD was diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease criteria.1 All COPD patients and control subjects were randomly enrolled from the outpatient clinic of Osaka City University Hospital. Because all COPD patients were aged >50 years, we also recruited controls in that age group, who had no history of any respiratory diseases. Physical examinations, anthropometric measurements including body mass index (BMI) and fat-free mass index (FFMI), assessment of pulmonary function and blood sampling were performed in all subjects. A spirometer (Chestac-25F, Chest Co., Tokyo, Japan) was used to obtain spirometric measurements.20 The diffusing capacity of the lung for carbon monoxide (DLCO) was measured by the single-breath carbon monoxide method at least twice. For all COPD patients, no medication was administered during the 24-h period preceding the pulmonary function test. Subjects with concomitant confounding diseases such as severe endocrine disorders were excluded. This study was approved by the institutional review board of Osaka City University (approval number: 2633), and all patients gave written informed consent. All procedures were performed according to the research ethics of the Declaration of Helsinki.
BMI and FFMI assessment BMI was calculated as kilograms per square metre. FFM was measured by bioelectrical impedance analysis (the Inbody 3.0 System Analyzer; Biospace, Tokyo, Japan). FFM was standardized for height and expressed as the FFMI (FFM/m2). The 6-min walk test On the same day as blood sampling, the 6-min walk test was performed according to international guidelines.21 Physical activity assessment All study subjects completed a self-administered questionnaire requesting information about physical activity, which check by the medical staff. Physical activity was graded in four levels as previously described.22 Exercise training Fifteen COPD patients agreed to perform a symptomlimited incremental exercise test. Eight COPD patients subsequently performed exercise training for 8 weeks as previously described.23 An upright cycle ergometer was used in the exercise training. Each patient performed the constant work rate training for 10 min three times a day. Serum irisin level in these patients was measured before, just after incremental exercise test, and 8 weeks after exercise training. The remaining seven COPD patients discontinued the exercise during the 8-week trial after the first incremental exercise test, and serum irisin levels were also measured before, just after incremental exercise test and 8 weeks after the first incremental exercise test. Measurement of serum irisin level Irisin levels in serum were assayed by using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Phoenix Pharmaceuticals, Burlingame, CA, USA). Statistical analysis Statistical analyses were performed using JMP version 10.0.0 software for Windows (SAS Institute Inc., Cary, NC, USA). All values are expressed as median (interquartile range). When comparisons of nonparametric data were performed between groups, a Mann–Whitney U-test was used. Differences between values before and after 8-week exercise training were determined by calculating the mean differences with a 95% confidence interval (CI); a paired t-test was used to compare group means. The significance of correlations was evaluated by determining Spearman’s rank correlation coefficients. In all statistical analysis, a P-value < 0.05 was considered significant.
RESULTS Clinical characteristics of study subjects Table 1 presents the clinical characteristics of study subjects. Age, BMI and FFMI between the two study
© 2015 The Authors Respirology (2015) 20, 612–617 Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology
614 Table 1
N Ijiri et al. Clinical characteristics of study subjects Control subjects
Subject number (male/female) Age (year) Smoking index (pack-year) BMI (kg/m2) FFMI (kg/m2) FEV1/FVC (%) FEV1 (%predicted) DLCO (%)
COPD patients
27 (24/3)
72 (65/7)
70 (62–75) 0
70 (66–74) 53 (33–64)
Table 2 Correlations of 6-min walk distance and serum irisin level with anthropometric measurements in patients with COPD
6MWD Iirisin
22.2 (21.4–23.8) 17.0 (13.5–19.0) 75 (72–79) 82 (80–85) N.D.
22.0 (21.0–23.0) 16.9 (13.5–18.0) 53 (41–61)* 59 (49–68)* 52 (42–63)
r P r P
BMI
FFMI
FEV1/FVC
%FEV1
%DLCO
0.30 0.01 0.09 0.47
0.34 0.004 0.18 0.13
0.31 0.01 0.05 0.96
0.42
ORIGINAL ARTICLE
Irisin, a newly discovered myokine, is a novel biomarker associated with physical activity in patients with chronic obstructive pulmonary disease NAOKI IJIRI, HIROSHI KANAZAWA, KAZUHISA ASAI, TETSUYA WATANABE AND KAZUTO HIRATA Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
ABSTRACT Background and objective: Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise. Physical activity has been emphasized as one of the principal targets of the treatment for chronic obstructive pulmonary disease (COPD). This study was designed to evaluate the possibility of using serum irisin level as a novel biomarker associated with physical activity in patients with COPD. Methods: We measured the serum irisin level in 72 COPD patients and 27 control subjects, and investigated its correlation to pulmonary function parameters, exercise capacity and physical activity level. In addition, we analysed the effects of acute and chronic exercise on serum irisin level. Results: Fat-free mass index was not significantly different between the two study groups. However, lower serum irisin level was observed in COPD patients than in the control subjects (COPD patients: median (interquartile range) 31.6 (22.7–40.4) ng/mL; control subjects: 50.7 (39.3–65.8) ng/mL; P < 0.001). The serum irisin level did not significantly correlate with any pulmonary function parameters and 6-min walk distance. However, serum irisin level was associated with the physical activity level in all subjects. In COPD patients, acute exercise did not affect serum irisin level, but an 8-week exercise training was linked to the significant increase in its level. Conclusions: Circulating irisin could be used to evaluate physical activity in COPD patients and increased after an 8-week exercise training. Serum irisin level may prove to be a valuable biomarker in clinical follow up of COPD. Correspondence: Hiroshi Kanazawa, Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Email: [email protected] Received 18 September 2014; invited to revise 25 November and 23 December 2014; revised 10 and 25 December 2014; accepted 12 January 2015 (Associate Editor: Melissa Benton). Article first published online: 20 March 2015 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
SUMMARY AT A GLANCE Serum levels of irisin increased in COPD patients following an 8-week training programme. Serum irisin level could be used as a novel biomarker associated with physical activity in patients with COPD and may prove to be a valuable tool in clinical follow up of COPD.
Key words: 6-min walk distance, exercise, fibronectin type III domain-containing protein 5, irisin, physical activity. Abbreviations: 6MWD, 6-min walk distance; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity of the lung for carbon monoxide; ELISA, enzyme-linked immunosorbent assay; FFMI, fat-free mass index; FNDC5, fibronectin type III domaincontaining protein 5; WBV, whole body vibration.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible, usually progressive and associated with an abnormal inflammatory response of the lung.1 It has been widely recognized to include a variety of extrapulmonary complications that may contribute to its severity.2 For example, patients with COPD often experience weight loss associated with muscle atrophy, which is thought to have adverse effects on physical activity and to be one of the independent risk factors for mortality.3 The patients frequently complain of dyspnoea related to various routine tasks and may find themselves in a downward spiral of symptom-related inactivity, leading to deconditioning and muscle weakness.4,5 Physical activity is an important clinical parameter in many chronic diseases including COPD.6 Limited physical activity has been associated with more frequent hospitalization caused by exacerbations in COPD; furthermore, physical activity level has been shown to predict mortality in these patients.7 The physical activity reported by individual patients has
© 2015 The Authors Respirology (2015) 20, 612–617 Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology doi: 10.1111/resp.12513
613
Circulating irisin in COPD
been recognized as one of the principal targets of treatment for COPD.8 Thus, quantifying physical activity in daily life, together with its intensity and frequency, is of great value. To date, physical activity can be evaluated by self-report questionnaires, as well as by using motion sensors.9–12 Because the daily average of these data in individual patients is not simple to evaluate, a specific and stable biomarker of physical activity in patients with COPD is required for wide use in clinical follow up of the disease. Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise.13–15 It is regulated by peroxisome proliferator-activated receptor-γ coactivator-1-α and is proteolytically processed from the product of the fibronectin type III domaincontaining protein 5 (FNDC5) gene prior to being released into the circulation.16,17 Thus, irisin could be a rational biomarker for diseases linked with physical inactivity.18,19 Therefore, the present study was designed to compare serum irisin levels between patients with COPD and control subjects, and investigate the correlations to pulmonary function parameters, exercise capacity and physical activity in COPD patients. In addition, we analysed the effects of acute and chronic exercise on serum irisin level in affected patients.
METHODS Study subjects Seventy-two patients with COPD and 27 control subjects were recruited into the study. All COPD patients were former smokers having a previous smoking history >20 pack-years, and all control subjects were never-smokers. COPD was diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease criteria.1 All COPD patients and control subjects were randomly enrolled from the outpatient clinic of Osaka City University Hospital. Because all COPD patients were aged >50 years, we also recruited controls in that age group, who had no history of any respiratory diseases. Physical examinations, anthropometric measurements including body mass index (BMI) and fat-free mass index (FFMI), assessment of pulmonary function and blood sampling were performed in all subjects. A spirometer (Chestac-25F, Chest Co., Tokyo, Japan) was used to obtain spirometric measurements.20 The diffusing capacity of the lung for carbon monoxide (DLCO) was measured by the single-breath carbon monoxide method at least twice. For all COPD patients, no medication was administered during the 24-h period preceding the pulmonary function test. Subjects with concomitant confounding diseases such as severe endocrine disorders were excluded. This study was approved by the institutional review board of Osaka City University (approval number: 2633), and all patients gave written informed consent. All procedures were performed according to the research ethics of the Declaration of Helsinki.
BMI and FFMI assessment BMI was calculated as kilograms per square metre. FFM was measured by bioelectrical impedance analysis (the Inbody 3.0 System Analyzer; Biospace, Tokyo, Japan). FFM was standardized for height and expressed as the FFMI (FFM/m2). The 6-min walk test On the same day as blood sampling, the 6-min walk test was performed according to international guidelines.21 Physical activity assessment All study subjects completed a self-administered questionnaire requesting information about physical activity, which check by the medical staff. Physical activity was graded in four levels as previously described.22 Exercise training Fifteen COPD patients agreed to perform a symptomlimited incremental exercise test. Eight COPD patients subsequently performed exercise training for 8 weeks as previously described.23 An upright cycle ergometer was used in the exercise training. Each patient performed the constant work rate training for 10 min three times a day. Serum irisin level in these patients was measured before, just after incremental exercise test, and 8 weeks after exercise training. The remaining seven COPD patients discontinued the exercise during the 8-week trial after the first incremental exercise test, and serum irisin levels were also measured before, just after incremental exercise test and 8 weeks after the first incremental exercise test. Measurement of serum irisin level Irisin levels in serum were assayed by using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Phoenix Pharmaceuticals, Burlingame, CA, USA). Statistical analysis Statistical analyses were performed using JMP version 10.0.0 software for Windows (SAS Institute Inc., Cary, NC, USA). All values are expressed as median (interquartile range). When comparisons of nonparametric data were performed between groups, a Mann–Whitney U-test was used. Differences between values before and after 8-week exercise training were determined by calculating the mean differences with a 95% confidence interval (CI); a paired t-test was used to compare group means. The significance of correlations was evaluated by determining Spearman’s rank correlation coefficients. In all statistical analysis, a P-value < 0.05 was considered significant.
RESULTS Clinical characteristics of study subjects Table 1 presents the clinical characteristics of study subjects. Age, BMI and FFMI between the two study
© 2015 The Authors Respirology (2015) 20, 612–617 Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology
614 Table 1
N Ijiri et al. Clinical characteristics of study subjects Control subjects
Subject number (male/female) Age (year) Smoking index (pack-year) BMI (kg/m2) FFMI (kg/m2) FEV1/FVC (%) FEV1 (%predicted) DLCO (%)
COPD patients
27 (24/3)
72 (65/7)
70 (62–75) 0
70 (66–74) 53 (33–64)
Table 2 Correlations of 6-min walk distance and serum irisin level with anthropometric measurements in patients with COPD
6MWD Iirisin
22.2 (21.4–23.8) 17.0 (13.5–19.0) 75 (72–79) 82 (80–85) N.D.
22.0 (21.0–23.0) 16.9 (13.5–18.0) 53 (41–61)* 59 (49–68)* 52 (42–63)
r P r P
BMI
FFMI
FEV1/FVC
%FEV1
%DLCO
0.30 0.01 0.09 0.47
0.34 0.004 0.18 0.13
0.31 0.01 0.05 0.96
0.42
