Physical inactivity is associated with decreased growth differentiation factor 11 in chronic obstructive pulmonary disease

Figures & data

Table 1 Characteristics of the study subjects

	Control	COPD
		GOLD I/II	GOLD III/IV
Subjects, n	18	37	33
Age, years	69.2±6.2	70.1±5.5	71.2±6.2
Males/females	17/1	36/1	33/0
Smoking, pack-years	30.5±11.4	60.0±27.5*	61.3±30.5*
BMI, kg/m^2	24.0±3.2	23.6±3.2	21.0±3.5*,‡
mMRC dyspnea score	0.1±0.2	0.9±0.8*	1.9±1.0*,‡
FVC, % predicted	108.3±12.7	99.5±16.0	73.6±19.0*,‡
FEV1, % predicted	103.0±13.1	70.8±12.2*	32.6±10.8*,‡
FEV1/FVC, %	77.5±4.4	58.1±9.0*	35.7±8.7*,‡
IC, L	2.8±0.5	2.3±0.4*	1.8±0.5*,‡
DLco’, % predicted	112.3±27.1	70.0±25.4*	43.2±22.6*,‡
6MWD, m	510 (470–558)	450 (400–484)*	350 (208–402)*,‡
LABA, n	–	23	29
LAMA, n	–	27	33
ICS, n	–	8	11

Notes: Data are presented as mean ± SD or median (IQR).

* p < 0.01 versus control,

‡ p < 0.01 versus GOLD I/II.

Abbreviations: BMI, body mass index; D_Lco’, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroids; IQR, interquartile range; LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; 6MWD, 6-minute walking distance.

Figure 1 Correlations between the levels of GDF11 and lung function data.

Notes: Correlations between the levels of plasma GDF11 and the values of FEV₁ % predicted (A), FVC % predicted (B), IC (C), and D_Lco’ % predicted (D) were investigated. Data were statistically analyzed by the Spearman’s rank test. Closed circles (gray): GOLD stage I/II; closed circles (black): GOLD stage III/IV.
Abbreviations: D_Lco’, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GDF11, growth differentiation factor 11; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity.

Table 2 Physical activity in the study subjects

	Control	COPD
		GOLD I/II	GOLD III/IV
Subjects, n	18	37	33
Number of steps per day	6,844 (4,935–7,832)	5,460 (2,527–7,840)	1,744 (716–4,543)**,‡
Duration of ≥2.0 METs, min/day	177 (143–254)	162 (92–225)	83 (58–157)*,‡
Duration of ≥2.5 METs, min/day	84 (63–143)	71 (35–95)	27 (11–62)**,‡
Duration of ≥3.0 METs, min/day	37 (25–51)	25 (12–43)	8 (3–19)**,‡

Notes: Data are presented as median (IQR).

* p < 0.01,

** p < 0.001 versus control,

‡ p < 0.01 versus GOLD I/II.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; METs, metabolic equivalents; IQR, interquartile range.

Figure 2 Correlations between the levels of GDF11 and physical activity.

Notes: Correlations between the levels of plasma GDF11 and parameters of physical activity including the number of steps (A), duration of ≥2.0 METs (B), ≥2.5 METs (C), and ≥3.0 METs (D) were investigated. r is the correlation coefficient. Data were statistically analyzed by the Spearman’s rank test. Closed circles (gray): GOLD stage I/II; closed circles (black): GOLD stage III/IV.
Abbreviations: GDF11, growth differentiation factor 11; GOLD, Global Initiative for Chronic Obstructive Lung Disease; METs, metabolic equivalents.

Figure 3 Correlations between the levels of GDF11 and muscle strength and exercise capacity.

Notes: Correlations between the levels of plasma GDF11 and the QMVC % predicted (A) and the 6MWD (B) were investigated. r is the correlation coefficient. Data were statistically analyzed by the Spearman’s rank test. Closed circles (gray): GOLD stage I/II; closed circles (black): GOLD stage III/IV.
Abbreviations: GDF11, growth differentiation factor 11; GOLD, Global Initiative for Chronic Obstructive Lung Disease; 6MWD, 6-minute walking distance; QMVC, quadriceps maximal voluntary contraction.

Figure 4 Correlations between the levels of GDF11 and systemic inflammatory markers.

Notes: Correlations between the levels of plasma GDF11 and the amounts of IL-6 (A), hs-CRP (B), fibrinogen (C), and MDA (D) were investigated. r is the correlation coefficient. Data were analyzed by the Spearman’s rank test. Closed circles (gray): GOLD stage I/II; closed circles (black): GOLD stage III/IV.
Abbreviations: GDF11, growth differentiation factor 11; GOLD, Global Initiative for Chronic Obstructive Lung Disease; hs-CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; MDA, malondialdehyde.

Table 3 Single regression analysis of plasma GDF11 in COPD patients

Variables	GDF11
	β*	p-value
Age (years)	−0.33	0.611
Smoking	−0.06	0.576
FVC % predicted	0.64	<0.001
FEV1 % predicted	0.43	<0.001
IC	0.66	<0.001
DLco’ % predicted	0.31	0.001
6MWD	0.48	<0.001
Number of steps	0.28	<0.001
IL-6	−0.21	0.020
QMVC % predicted	0.64	<0.001

Notes:

* β = regression coefficient. All data were log transformed. Data were analyzed by single linear regression analysis.

Abbreviations: D_Lco’, diffusing capacity of the lung for carbon monoxide; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GDF11, growth differentiation factor 11; IC, inspiratory capacity; IL-6, interleukin-6; 6MWD, 6-minute walking distance; QMVC, quadriceps maximal voluntary contraction.

Table 4 Multiple regression analysis of plasma GDF11 in the COPD patients

Variables	GDF11
	β*	p-value
Smoking	0.23	0.078
FEV1 % predicted	0.05	0.735
6MWD	0.02	0.908
Number of steps	0.20	0.045
IL-6	−0.01	0.909
QMVC % predicted	0.31	0.093

Notes:

* β = regression coefficient. All data were log transformed. Data were analyzed by multivariate linear regression. R² =0.50 (adjusted R² =0.42).

Abbreviations: FEV₁, forced expiratory volume in 1 second; GDF11, growth differentiation factor 11; IL-6, interleukin-6; 6MWD, 6-minute walking distance; QMVC, quadriceps maximal voluntary contraction.

Figure S1 Levels of GDF11 in plasma.

Notes: Plasma was obtained from the control subjects, GOLD stage I/II and GOLD stage III/IV COPD patients. The levels of plasma GDF11 were investigated by immunoblotting (A). Ponceau S staining was used to evaluate the amounts of protein. The GDF11 levels were calculated by measuring the intensity of the bands (B). Open circles: control; closed circles (gray): GOLD stage I/II; closed circles (black): GOLD stage III/IV. Results are expressed mean ± SD. Data were analyzed with one-way ANOVA followed by Tukey’s test. ***p < 0.001 compared with control; +++p < 0.001 compared with GOLD stage I/II.

Abbreviations: ANOVA, analysis of variance; GDF11, growth differentiation factor 11; GOLD, Global Initiative for Chronic Obstructive Lung Disease; M, molecular weight marker.