Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis

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Abstract

In recent years it has become clear that multiple sclerosis (MS) patients benefit from physical exercise as performed in aerobic training but little is known about the effect on functional domains and physiological factors mediating these effects. We studied immunological, endocrine and neurotrophic factors as well as coordinative function and quality of life during an 8-week aerobic bicycle training in a waitlist control design.

In the immune-endocrine study (1) 28 patients were included, the coordinative extension study (2) included 39 patients. Training was performed at 60% VO2max after determining individual exertion levels through step-by-step ergometry. Metabolic (lactate), endocrine (cortisol, adrendocortico-releasing hormone, epinephrine, norepinephrine), immune (IL-6, soluble IL-6 receptor), and neurotrophic (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF)) parameters were compared from a prestudy and a poststudy endurance test at 60% VO2max for 30 min.

In study (1), lowered lactate levels despite higher workload levels indicated a training effect. Disease-specific quality of life (as measured by the Hamburg Quality of Life Questionnaire for Multiple Sclerosis, HAQUAMS) significantly increased in the training group. No significant training effects were seen for endocrine and immune parameters or neurotrophins. In study (2), two out of three coordinative parameters of the lower extremities were significantly improved. In summary, low-level aerobic training in MS improves not only quality of life but also coordinative function and physical fitness.

Introduction

Multiple sclerosis (MS) is a heterogeneous chronic disease of the central nervous system characterized by different patterns of inflammation, demyelination and axonal loss [1] predominantly affecting young adults in their most productive years. Since the observations of Uhthoff [2], MS patients have been advised to avoid physical activity because symptoms may worsen with an elevated body temperature. Due to these observations and due to their disability most MS patients show a very low level of physical activity, which increases weakness, fatigue and other health risks in a vicious circle. Since the first studies in 1984 [3], it has become clear that MS patients benefit from exercise (for review, see Ref. [4]). It has been shown that fitness levels and quality of life improved. Depressive symptoms and fatigue, which are highly relevant for quality of life, were similarly influenced by training. One study also reported an effect on gait performance [5]. However, other clinical relevant indicators of physical function as e.g. balance and coordination have not been studied systematically in MS. Furthermore, the mechanisms of these effects are unclear.

Acute exercise represents a mild physical stressor and has an array of effects on immune and endocrine parameters depending on the type (eccentric or concentric) and extent (mild vs. strenuous) of the training (for review, see Ref. [6]). In contrast to a large number of studies on the immune response to acute exercise, much less is known concerning the effect of physical conditioning or training on immune function or endocrine factors. Studies in healthy subjects have shown that exercise-training increases NK cell count and cytolytic activity (for review, see Ref. [7]). Recently, Smith et al. [8] demonstrated that 6 months of fitness training lowers proinflammatory cytokine activity in cardiovascular disease patients. They assume an anti-atherogenic effect through these factors. Only very few studies investigated training effects in autoimmune diseases [9].

Studies in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, have shown that exercise during the induction phase of the disease does not aggravate the course of disease [10]. None of the clinical MS studies mentioned above reported enhancement of the inflammatory activity or exercise-induced exacerbations (for review, see Ref. [11]). However, endocrine or immunological markers have not been analyzed yet. Recent data from cross-sectional findings of our study indicate that MS patients show a slightly hyporeactive cytokine response to acute physical exercise compared to controls while endocrine responses were not altered [12].

Acute exercise has been shown to promote neurogenesis and neurotrophic factors such as brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) in animals [13]. Thus exercise might have a restorative potential. We recently demonstrated that BDNF and NGF could be induced in the serum of healthy subjects and MS patients during acute exercise [14]. However, the longitudinal effects of training programs on these factors are unknown.

Therefore, we studied physical (i.e. fitness and coordinative functions) and quality of life parameters (especially depressive symptoms and fatigue) as well as neurotrophic responses to fitness training in a longitudinal randomized study design. Endocrine factors of the major stress response systems, i.e. the HPA axis (ACTH, Cortisol) and the sympathetic nervous system (adrenaline, noradrenaline) were also analyzed. We chose IL-6 and soluble IL-6 receptor (sIL-6R) as immune parameters. The IL-6/sIL6R system has been described as induced in stress conditions and especially in exercise [15]. It is furthermore closely connected to the hypothalamic–pituitary–adrenal (HPA) axis inducing CNS stress responses.

We conducted a highly standardized bicycle training of 8 weeks in a waitlist control group design. Based on the results from previously published studies, we expected improved quality of life, coordinative function and psychological functioning (i.e. amelioration of depressiveness and fatigue). Furthermore, we hypothesized that ergometry training might lower inflammatory cytokine activity and catecholamine responses. We also predicted increased levels of neurotrophic factors in peripheral blood.

Section snippets

Subjects

We recruited a group of MS patients (n=46) who underwent an inclusion test (see below) and were randomized later to an exercise or a control group. From the original sample of 46 MS patients, 18 subjects had to be excluded from the immune-endocrine study, as they did not reach at least 100 W or interrupted the endurance test (see below) more than 5 min earlier than required. To increase patient recruitment we decided to separate study (2) and offered the study of coordinative function also to

Demographic data (see Table 1)

There were no significant differences between the training and control groups in sex distribution, age, height, or with respect to training experience (all values p>0.10). Mean disease duration in the MS cohort was 11.4±1.6 years and subjects had an EDSS score of 2.3±0.2 on average. Study (1) comprised 19 patients with relapsing–remitting disease, 5 with secondary progressive MS and 2 with primary progressive MS. In study (1) disease activity scores as measured with the CAMBS did not differ

Discussion

In this study of an 8-week low-level bicycle exercise training we could demonstrate a beneficial effect on a parameter of physical fitness, quality of life parameters and in an extension study improved coordinative function. There is also some indication that some biological parameters such as sIL-6R and neurotrophines may be affected by such training interventions.

Acknowledgement

This research was supported by grants from the Gemeinnützige Hertie Stiftung (Grant No. 1.319.110-01-06 and Grant No. 1.319.120-01-01). The authors would like to thank Sten Hartmann, Mila Mladek and Alice Ludwig for their invaluable help in the acquisition of the data. The laboratory tests would not have been possible without the excellent laboratory expertise of Wiebke Tessmer and Christine Dieu. We are very grateful to Sabine Quandte for her exceptional help in the preparation of the

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    KHS and SMG contributed equally to the manuscript.

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