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

Anja Mähler,Markus Kleinewietfeld,Urša Šušnjar,Ilona Csizmadia,Dominik N Müller,Friedemann Paul,Lars Klug,Michael Boschmann,Jochen Steiniger,Andras Balogh

doi:10.3389/fimmu.2018.02819

Abstract

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.Clinical Trial Registration: ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.gov

Highlights

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation and neurodegeneration within the central nervous system [1]
Total increase in EE within 40 min exercise did not differ between the groups, indicating comparable fitness levels at baseline
We focused on CD4+ regulatory T cell (Treg) and CD4+ T helper cell (Th) populations

Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation and neurodegeneration within the central nervous system [1]. Erythropoietin is thought to act as a neuroprotective agent in MS. Its application delayed disease onset, reduced inflammation and clinical scores in acute EAE in rats [9] and exerted positive effects in a small study on progressive MS patients [10] and as add-on therapy in acute optic neuritis [11]. 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. 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

Results

Discussion

Conclusion