Why do we need to do the study? Currently available pharmacological treatments do not improve multiple sclerosis (MS) symptoms, such as weakness. Exercise training improves multiple symptoms associated with MS, including weakness, fatigue, and mood problems. Global metabolomics is a technology that allows us to measure hundreds of metabolites in blood. Exercise can alter multiple metabolic pathways, and some of these changes may be responsible for the beneficial effects of exercise. Our preliminary studies show that metabolomics reveals differences in the metabolic profile between people with MS and healthy individuals. We also show that metabolomics can be used to study the effect of a treatment on the metabolic profile of people with MS. We propose that the effects of exercise in people with MS may be mediated through its metabolic effects and that, utilizing metabolomics, we can link changes in the metabolic profile to changes in MS-related symptoms.

What are the goals of the study? We aim to first identify metabolic alterations produced by strength training in people with MS and healthy individuals. We will then determine whether strength training improves abnormal metabolic pathways in people with MS. We will also determine the relationship between changes in metabolites and change in measures of MS symptom severity, before and after the exercise intervention.

How will the study be conducted? This study will include 20 adults with relapsing remitting MS who meet the inclusion and exclusion criteria and 20 healthy controls of similar age and gender. Participation will involve two study visits separated by 12 weeks of Progressive Resistance Training (PRT), which will consist of 12 weeks of guided PRT three times weekly. We will record details of duration, repetitions, and resistance levels of PRT achieved by each participant to help us compare the amount of exercise performed by each participant. We will also measure the severity of MS-related symptoms such as fatigue, strength, physical fitness, cognition, and overall impairment at the beginning and end of the study. At each of these visits, we will obtain blood for metabolomics analysis, and at the end of the study these samples will undergo global untargeted metabolomics analysis at Metabolon, Inc., Durham, NC. This will involve preparation of samples and identification and measurement of metabolites using a gas/liquid chromatography and mass spectrometry platform. The metabolite concentration obtained will then undergo transformation using a method to identify groups of metabolites that are tightly linked to each other. We will then identify which of these groups of metabolites changes with exercise in people with MS and in healthy individuals. We will also assess whether exercise improves the abnormalities noted in the metabolic profiles of people with MS compared to healthy individuals at the beginning of the study. Finally, we will test whether the change in these metabolite groups is linked to change in MS symptoms. This will identify the metabolites that are related to change in the severity of MS-related symptoms.

How is the study innovative? While the beneficial effects of exercise on MS-related symptoms are known, the mechanisms by which exercise produces these effects are not well understood. We propose to use an innovative technology -- metabolomics, to investigate the effects of an exercise intervention on the metabolic profile of MS patients.

What is the likely impact of the study? This study has the potential to identify mechanisms by which exercise impacts the metabolic profile in MS patients. This information could help in personalizing care by helping to individualize exercise interventions for people with MS. Additionally, identification of metabolic pathways that are associated with improvement in symptoms could lead to development of alternative treatment strategies that target these pathways. In the long run, this could lead to new strategies for the treatment of MS-related symptoms and improve the quality of life for people with MS.