Metabolic, mental and immunological effects of normoxic and hypoxic training in multiple sclerosis patients: a pilot study

Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells. Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed. Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P < 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39(+) and CD31(+) Tregs, respectively, and decreased IL-17A-producing CD4(+) cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group. Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin

Metabolic, Mental and Immunological Effects of Normoxic and Hypoxic Training in Multiple Sclerosis Patients: A Pilot Study

Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells.Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed.Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P &lt; 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39+ and CD31+ Tregs, respectively, and decreased IL-17A-producing CD4+ cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group.Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin.Clinical Trial Registration: ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.go

Study design.

<p>PAL, physical activity level; BMI, body mass index.</p

Adipose tissue and skeletal muscle microdialysis.

<p>(A, B) Ethanol ratio and dialysate concentrations of (C, D) glucose, (E, F) lactate, and (G, H) glycerol in adipose tissue and skeletal muscle in MS patients (adipose, n = 15; muscle, n = 16) and in control subjects (n = 16) before and after an oral glucose load. Data are given as means ± SEM. <i>P</i> values in graphs indicate group differences; group*time interaction effects were significant in adipose for lactate (<i>P</i> = 0.0225) and glycerol (<i>P</i> = 0.0001), all by Brunner analysis.</p

Systemic energy metabolism measured by indirect calorimetry (canopy device).

<p>(A) Energy expenditure (EE, relative changes), (B) respiratory quotient (RQ), (C) carbohydrate oxidation (COX) and (D) lipid oxidation (LOX) in MS patients (n = 16) and control subjects (n = 14) before and after an oral glucose load. The elevated RQ value in MS patients indicates increased carbohydrate oxidation. Data are given as means ± SEM. Group difference <i>P</i> value in graph, group*time interaction effects for RQ <i>P</i> = 0.0008, COX <i>P</i> = 0.0016, LOX <i>P</i> = 0.0009, all by Brunner analysis.</p

Demographic and anthropomorphic characteristics of MS patients and control subjects^a.

a<p>Data are given as means ± SD (total range) unless stated otherwise. BMI denotes body mass index, WHR waist-to-hip ratio, PAL physical activity level, EDSS extended disability status scale, and n/a not applicable.</p>b<p>Median (total range).</p

Systemic energy metabolism measured by indirect calorimetry (metabolic chamber).

<p>(A) Energy expenditure (EE) and (B) respiratory quotient (RQ) in MS patients (n = 12) and control subjects (n = 12) at rest and during bicycle exercise after an oral glucose load (OGL). EE after 40 min of exercise <i>P</i> = 0.0243, by Mann-Whitney-U test.</p

Systemic responses to oral glucose load.

<p>Serum (A) glucose, (B) insulin, and (C) free fatty acids (FFA) in MS patients (n = 16) and in control subjects (n = 16) before and after an oral glucose load. Data are given as means ± SEM. (Conversion factors to convert to Metric Units (mg/dL) are as follows: 18.02 for glucose, 0.028 for FFA).</p