Background
Fibromyalgia (FM) is characterised by persistent widespread pain and increased pain sensitivity and tenderness [
1], and is associated with impaired physical fitness [
2]. Pain in FM is attributed to central sensitization and impaired pain inhibition [
3], implying that the pain increases during physical activities. Activity-induced pain in FM [
4] is a probable reason why persons with FM commonly prefer physical activities of low, rather than of high intensity [
5,
6].
Studies have shown that physical capacity can be improved through exercise in patients with FM [
7]. There are, however, several factors, such as age, sex, health and hormonal status, inflammation and nutrition that can influence the effect of exercise. Growth hormone has been of special interest in research of FM, due to documented disturbance in the pituitary growth hormone axis in FM, especially in persons with severe symptoms [
8,
9]. Growth hormone is influenced by several factors, such as sleep, stress, nutrition, smoking, body composition and physical activity [
10]. Growth hormone exerts its effect via the insulin-like growth factor (IGF) system in the liver including total and free IGF-,1 IGF-2 and six binding proteins (IGFBP) of which IGF-1 and IGFBP-3 are most important in the skeletal muscle [
11] with positive outcomes of exercise [
12] . Furthermore, exercise has beneficial effects in the central nervous system via uptake of peripheral IGF-1 [
13]. S-IGF-1 increased in lean women with FM, but not in overweight counterparts, after aerobic exercise twice weekly during 15 weeks [
14].
Acute release of IGF-1 in relation to exercise has not previously been studied in women with FM. The aim was to study the effects of short bouts of aerobic exercise of moderate and high intensities, respectively, on S-IGF-1 in women with FM in comparison with healthy controls.
The two exercise tests on an ergometer cycle
The exercise tests were conducted on a Monark ergometer cycle model 829 E (Monark, Vansbro, Sweden) and the load for each patient was chosen after an interview regarding the participant’s physical activity level to fit a given level on the Borg’s scale of perceived exertion (RPE scale) [
17]. Heart rate, blood pressure and rate of perceived exertion [
17] were monitored during the test. After 15-min of ergometer cycle test, the second blood test was sampled, after which the test person was asked to rate her pain and fatigue. Similar examinations were conducted after 30 min of rest (0–45 min).
Ergometer cycle test of moderate and high intensities
A 15-min test on a ergometer bicycle [
18] was performed and the participant was asked to rate her exertion on RPE scale. Moderate intensity was defined as 12–13 and high 15–17 on the RPE-scale, respectively [
17]. During the first test the patients also mentally adjusted themselves to manage the second test.
Exercise load
The load (watt) during ergometer cycling was monitored every other minute and adjusted to fit the participant’s perceived exertion level: i:e: 12–13 or 15–17, respectively, on the RPE-scale. The loads (watts) during the test performance were transformed to kilojoules to represent the total work during the test performance.
Pain threshold was examined by using an algometer (Somedic Production AB, Sollentuna, Sweden), measured in kilopascals (kPa) [
19]. The pain threshold was measured in two tender-point locations in the upper and lower extremities, respectively: musculus trapezius, musculus supraspinatus, musculus gluteus and medial fat pad of the knee [
1] . The mean value was applied, and a higher value indicated a better health.
Pain and fatigue were rated on a visual analogue scale (0–100; low to high). A higher score indicates more severe pain or fatigue.
Health status was assessed by the Fibromyalgia Impact Questionnaire (FIQ), a higher score indicating more severe impairment [
20].
Blood sampling
Serum samples were collected from the cubital vein in the fasting state at rest at baseline (0), after 15 min cycling and 30 min of rest after the bicycling was terminated (45 min). Biological markers were analyzed by sandwich enzyme-linked immunosorbent assays (ELISAs) using a pair of specific antibodies for human interleukin 8 (M1918, 1.0 pg/ml, Sanquin reagents, Amsterdam, the Netherlands). ELISAs were read with a Spectramax 340 from Molecular Devices (Sunnyvale, CA, USA). Human high sensitivity C-reactive protein (sCRP, ref < 5 μg/ml) was analyzed by immunoturbidimetic analysis by the accredited Laboratory for Clinical Chemistry at the Sahlgrenska University Hospital, Gothenburg, Sweden. Total S-IGF-1 was measured by solid-phase, enzyme-labeled chemoluminescent immunoassay with IDS-iSYS IGF1 immunoassay (IS-3900, Immunodiagnostic Systems Boldon, UK), S-IGFBP-3 and free IGF-1 with reagents from DY675, RnD Systems, Minneapolis, MN, USA.
Statistics
Non-parametric statistic tests were chosen due to small sample sizes. Descriptive data were presented as mean and SD or median and range. Differences within a group were analyzed by the Wilcoxon signed rank test and between the groups with Mann Whitney U-test. Fischer’s exact test was applied in the analysis of categorical data. Relations between the variables were examined with the Spearman’s correlation test. All significant tests were two-tailed, and values of p < 0.05 were considered significant.
Results
Study population
A total of 28 women with FM were screened for the study. Three of them did not fulfill the American College of Rheumatology 1990 criteria for FM and one had a high blood pressure, leaving 24 patients. Two patients withdrew themselves from the study due to time limitations. Thus, the patient population comprised 22 women with FM, with the mean age of 44 (range 33–50) years. The healthy reference group for the exercise tests comprised 27 women, mean age 44 years (range 29–50) years (ns). Anthropometric and background data are given in Table
1.
Table 1
Background data for women with fibromyalgia (FM) and the healthy reference group
Age, year | 44 | 4 | 33–50 | 44 | 5 | 29–50 | 0.808 |
BMI, kg/m2
| 28.2 | 5.3 | 20.5–38.9 | 23.2 | 2.7 | 18.8–31.2 | <0.001 |
Fat, kg | 28.3 | 12.0 | 11–51 | 17.6 | 8.0 | 4–40 | 0.001 |
Fat free mass, kg | 47.8 | 7.0 | 38–63 | 47.9 | 5.4 | 39–60 | 0.695 |
Tender points, 0–18 | 13 | 1.8 | 11–16 | 0 | 0 | 0 | <0.001 |
Pain localisations, 0–18 | 13 | 3.4 | 6–18 | 1.0 | 1.4 | 0–5 | <0.001 |
Algometry, kPa | 255 | 56 | 167–403 | 378 | 107 | 173–566 | <0.001 |
Smoking, yesa
|
N = 2 | | 0–2 |
N = 0 | | 0 | 0.186 |
Sleep quantity, 1–4 | 2.8 | 0.9 | 1–4 | 2.1 | 0.6 | 1–3 | 0.003 |
Sleep quality, 1–4 | 2.6 | 0.7 | 1–4 | 1.6 | 0.6 | 1–3 | <0.001 |
Work hours, 0–40 | 27 | 10.5 | 0–40 | 37 | 5.0 | 20–40 | <0.001 |
FIQ total score, 0–100 | 48 | 16 | 10–73 | 9 | 9 | 0–28 | <0.001 |
Hand force, maximum, right hand, N | 215 | 83 | 67–381 | 252 | 60 | 130–396 | 0.129 |
LTPAI, hours/week | 5.3 | 3.5 | 1–17 | 7.0 | 4.2 | 1–16 | 0.170 |
LTPAI, hard, hours/week | 0.6 | 1.3 | 0–6 | 1.4 | 1.4 | 0–6 | 0.024 |
Change in S-IGF-1
S-IGF-1 was similar in women with FM and controls at baseline and increased similarly in both groups, during the two exercise intensities. Mean response of S-IGF-1 was 6% in patients with FM during both the moderate and the high-intensity exercise. Mean response of IGF-1-t in the reference group was 7% during the moderate intensity exercise and 10% during the high-intensity exercise (ns between patients and controls), (Tables
2 and
3).
Table 2
Values obtained at moderate intensive exercise performance in women with fibromyalgia (FM) and the healthy reference group. Mean value and SD for baseline values, differences (∆), p-value for within-group differences as well as for between- group differences are presented
S-IGF-1 (ng/ml) | 178 ± 58 | 11 ± 10 | <0.001 | 179 ± 69 | 13 ± 10 | <0.001 | 0.825 | 0.629 |
free IGF-I (ng/ml) | 3.5 ± 1.6 | −0.15 ± 0.34 | 0.014 | 4.0 ± 2.09 | −0.38 ± 0.47 | <0.001 | 0.457 | 0.119 |
S-IGFBP3 (ng/ml) | 428 ± 44 | 11 ± 16 | 0.007 | 426 ± 37 | 14 ± 19 | 0.001 | 0.880 | 0.662 |
sCRP (μg/ml) | 2.0 ± 2.2 | 0.14 ± 0.18 | 0.001 | 0.56 ± 0.48 | 0.35 ± 0.46 | <0.001 | <0.001 | 0.215 |
IL-8 (pg/ml) | 9.2 ± 4.5 | −5.9 ± 1.6 | 0.105 | 9.6 ± 2.5 | −0.3 ± 1.0 | 0.077 | 0.769 | 0.600 |
Pain (0–100 mm) | 40 ± 19 | 7.6 ± 16 | 0.044 | 0.8 ± 2.1 | 2.0 ± 6.8 | 0.093 | <0.001 | 0.015 |
Fatigue in legs (0–100 mm) | 26 ± 23 | 28 ± 24 | <0.001 | 1 ± 2.4 | 6.0 ± 8.5 | 0.002 | <0.000 | <0.001 |
Fatigue global (0–100 mm) | 51 ± 27 | 9.2 ± 17 | 0.038 | 4 ± 6.4 | 10 ± 12 | 0.002 | <0.001 | 0.672 |
Table 3
Values obtained at high-intensity exercise performance in women with fibromyalgia (FM) (n = 22) and the healthy reference group (n = 27). Mean value and SD of differences (∆), p-value for within-group differences as well as for between- group differences are presented
S-IGF-1 (ng/ml) | 195 ± 60 | 11 ± 15 | <0.001 | 181 ± 66 | 19 ± 22 | <0.001 | 0.244 | 0.560 |
Free IGF-1 (ng/ml) | 4.7 ± 2.6 | −0.42 ± 0.48 | 0.014 | 4.7 ± 3.2 | −0.56 ± 0.76 | <0.001 | 0.755 | 0.843 |
S-IGFBP3 (ng/ml) | 556 ± 75 | 25 ± 37 | 0.009 | 614 ± 91 | 25 ± 41 | 0.008 | 0.037 | 0.942 |
sCRP μg/ml) | 2.1 ± 2.4 | 0.06 ± 0.16 | 0.002 | 0.70 ± 0.77 | 0.04 ± 0.06 | <0.001 | 0.001 | 0.119 |
IL-8 (pg/ml) | 7.5 ± 3.0 | 0.7 ± 2.9 | 0.545 | 9.7 ± 4.2 | −0.2 ± 1.9 | 0.673 | 0.107 | 0.565 |
Pain (0–100, mm) | 46 ± 24.4 | −4.0 ± 16.1 | 0.291 | 2.4 ± 7.4 | 0 ± 3.6 | 0.878 | <0.001 | 0.139 |
Fatigue in legs (0–100 mm) | 31 ± 21 | 28 ± 20 | <0.001 | 1.2 ± 3.1 | 12 ± 13 | <0.001 | <0.001 | 0.003 |
Fatigue global (0–100 mm) | 50 ± 24 | 8.4 ± 19 | 0.007 | 3.0 ± 5.3 | 6.3 ± 10 | <0.001 | <0.001 | 0.414 |
Change in S-IGFBP-3and free IGF-1
S-IGFBP-3 and free IGF-1 were similar in the two groups of women at baseline. S-IGFBP-3 increased and free IGF-1 decreased significantly during the two exercise intensities in women with FM and in controls (ns between groups), (Tables
2 and
3).
Change in IL-8 and sCRP
Serum IL-8 was similar in women with FM and controls at baseline and did not change during the exercise in any of the two groups (Tables
2 and
3).
sCRP levels were higher in women with FM compared with controls at baseline. sCRP increased during both exercise intensities in both groups (ns between groups), (Tables
2 and
3).
Body composition
Body mass index and body fat were higher in women with FM. However, lean mass was similar (Table
1). Lean mass did not correlate with S-IGF-1 (
p = 0.200) in any group.
In women with FM, body fat was correlated with pain (r = 0.434, p = 0.044, n = 22) and global fatigue (r = 0.57, p = 0.006, n = 22) at 15 min of high intensity exercise and the level of sCRP (r = 0.487, p = 0.022, n = 22). BMI correlated with global fatigue at 15 min of exercise (r = 0.514, p = 0.014, n = 22) and sCRP level (r = 0.465, p = 0.029, n = 22) and tended to correlate negatively with baseline levels of S-IGF (r = −0.415, p = 0.055) in women with FM. BMI or body fat did not correlate with change in S-IGF-1 at moderate or high intensity exercise, respectively, in women with FM.
Pain
Patients with FM reported more pain at baseline when compared to the reference group (
p < 0.001). Pain increased more in the women with FM during the moderate intensity exercise (Table
2), while there was no difference for change between the two groups during the high-intensity exercise (Table
3).
Pain threshold
Women with FM had significantly lower pain threshold measured with algometry at baseline, on both exercise occasions, when compared to the reference group (Table
1). No significant difference was found (
p = 0.66) when the baseline pain thresholds at the first and the second test occasion were compared within the FM-group. Pain thresholds decreased in the FM-group after moderate (−25 ± 20,
p < 0.0001) and tended to decrease after high intensity exercise (−12 ± 28,
p = 0.08). Pain thresholds increased after high (17 ± 38,
p = 0.02) but not after moderate intensity exercise in controls.
Fatigue in the legs, global fatigue
Women with FM reported more fatigue in the legs as well as global fatigue at baseline when compared to the reference group (
p < 0.001). Fatigue in the legs increased during both exercise intensities in both groups and was more pronounced in the FM-group than in the reference groups. Global fatigue increased in both groups during both exercise intensities, (ns between the two groups), (Tables
2 and
3).
Discussion
Growth hormone derived S-IGF-1 and its binding protein S-IGFBP-3 increased after moderate exercise during 15 min on an ergometer cycle in women with FM similar to women in the healthy reference group in spite of more reported pain and fatigue in FM. The mean increase in S-IGF-1 was in line with previous reports from healthy individuals [
21,
22].
Exercise mobilises systemic IGF-1 from the liver and locally in skeletal muscle. Growth hormone is the main stimulus for hepatic IGF-1 production in the resting state but there is a delay of several hours of growth hormone-mediated release of hepatic IGF-1 post-exercise [
23,
24]. This indicates that the increase in S-IGF-1 in this study was growth hormone-independent. It has been shown that circulating IGF-1 is mobilised from active muscles during intense exercise [
11,
25].
A higher level of S-IGF-1 has been associated with better physical fitness among both younger [
26] and older individuals [
27]. In healthy women, IGF-1 and ratio of IGF-1/IGFBP-3 were associated with maximum power output [
28]. Resting level of S-IGF-1 declines with aging together with sarcopenia and osteopenia [
10,
29], and it is low in chronic and severe diseases [
30]. An increase of S-IGF-1, ranging from ~10 to 30%, has been measured after 5–10 min of high-intensity bouts of exercise in healthy individuals [
21]. Mechanisms regulating the concentration of IGF-1 are complex, and the transient increase during a bout of exercise returns to baseline within one hour [
21]. This may involve uptake into peripheral tissues [
31] and uptake into the central nervous system [
32].
The reduced levels of free IGF-1 may be due to activity induced uptake of IGF-1 from the blood. IGF-1 is actively taken up from blood into the central nervous system via the blood brain barrier and via the choroid plexus. Uptake of IGF-1 over the blood brain barrier is stimuli-dependent and coupled with increased neuronal activity [
32]. Both aerobic exercise and systemic injection of IGF-1 increase cerebrospinal levels of IGF-1 without alterations in serum levels in rats [
13]. It has therefore been suggested that serum levels of IGF-1 may be rapidly normalized due to strong uptake into the brain [
33] and IGF-1 uptake may be increased by the physical activity. There is also evidence of re-uptake of IGF-1 into peripheral muscle after exercise [
31]. The present study would indicate that both mobilisation of IGF-1 into the blood and possible active re-uptake into tissues after exercise is preserved in FM patients. As expected, the patients with FM showed a lower pain threshold [
1] and higher ratings of pain and fatigue in legs and global fatigue at baseline. A notable increase of local fatigue was found already during exercise at moderate intensity. This finding is in line with a previous study reporting that physical exercise induces fatigue in FM [
34]. The lean mass, which mainly reflects the skeletal muscle mass, was similar in both groups of the present study. However, BMI and body fat content were higher in the patients than the controls. This might contribute to the higher self-reported fatigue, during exercise. In a previous study, increased levels of S-IGF-1 after 15 weeks of aerobic exercise was found in lean but not in overweight and obese patients with FM [
14]. Furthermore, BMI was associated with CRP in FM. This implies a peripheral low-grade inflammation and could potentially contribute to reduced muscular IGF-1 response in overweight women with FM [
35‐
37]. However, in the present study, BMI did not correlate with the acute IGF-1 response.
The exercise load was defined by means of the RPE scale, a method recommended for determining exercise intensity [
38]. The ratings of exertion showed that both groups followed the protocol at the two test occasions, without any significant differences for the rating of exertion, and therefore the groups were comparable. Walking on flat ground indoors with a velocity of 4 km/h for a person with a bodyweight of 70 kg corresponds to approximately 50 W. All the participants were able to carry on a normal conversation without any notable impact on their breathing rate. Thus, the exercise load corresponded to a moderate exercise level. In women with FM, the exercise load remained at 50 W also at the end of the exercise period.
Previous studies have shown that women with FM have a lower muscular physical fitness when compared to healthy women [
2,
39]. This might explain why women with FM cycled at a significantly lower exercise load than the healthy reference group in the present study. The patients with FM also reported less hours spent on vigorous exercise during their leisure time, compared to the reference group, in line with previous studies [
6].
Conclusions
Fifteen minutes of exercise at moderate intensity was sufficient to achieve an increase in total S-IGF-1 and its binding protein, S-IGFBP-3. Hence, patients with FM were able to activate their skeletal muscle metabolism during a short, moderate bout of exercise, despite of their pain and fatigue. This knowledge is of importance for clinical rehabilitation of patients with FM who commonly exercise at this level, rather than at a high intensity level.
Acknowledgements
We thank Karolina Thörn for her skillful technical assistance with immunological analysis of protein levels, and Sahlgrenska University Hospital/Physiotherapy, where the two exercise tests were conducted.