Little is known about the potential effects of exercise on the underlying disease mechanisms in multiple sclerosis (MS). Although contactin-1 and contactin-2 are known as two proteins involved in axonal regeneration, it is unclear whether these proteins are induced by exercise in persons with MS (PwMS). The aim of this study was to determine the serum levels of contactin-1 and contactin-2 in PwMS and to investigate the change of these markers with exercise. Although contactin-1 and contactin-2 are known as two proteins involved in axonal regeneration, the mechanism of action of these proteins in MS patients has not been fully elucidated in the literature. The investigators' aim was to determine the serum levels of contactin-1 and contactin-2 in a group of relapsing-remitting multiple sclerosis (RRMS) patients and to evaluate the change of these markers with exercise. Thus, the investigators think that a valuable contribution will be made to the literature to shed light on the role of biomarkers in the mechanism mediating the beneficial effects of exercise in MS. In addition, as far as the investigators know, this study is the first to investigate the effect of exercise on contactin-1 and contactin-2 serum levels in MS patients.

This randomized controlled trial with a blinded outcome assessment evaluated an 8-week (3 sessions per week) training intervention to determine the effect of exercise on contactin-1 and contactin-2 in persons with RRMS. The participants were divided into the intervention and control groups by stratified randomization. Stratification was randomly assigned as 1≤ EDSS ≤ 3 and 3< EDSS ≤5.5 using Windows-based SPSS 25.0. (SPSS Inc., Chicago, Illinois, USA). All measurements and tests were performed before and after the 8-week exercise program. Blood samples were taken for analysis of contactin-1 and contactin-2 serum levels, after which participants completed a cognitive performance and a cardiopulmonary exercise test.

The current study was approved by the Fırat University Human Research Ethics Local Committee (2021/12-38) and was conducted in accordance with the Declaration of Helsinki. All participants were informed about the study and their written informed consent was obtained before the study. Participants performed a graded cardiopulmonary exercise test on a cycle ergometer (Ergoline Ergoselect 200; Ergoline GMBH, Bitz, Germany) at the beginning to determine their maximum aerobic capacity. The test was stopped at the moment of voluntary exhaustion, when patients were unable to maintain cadence (<50 rpm), the maximum effort was achieved, or for safety reasons. Venous blood was drawn using venipuncture and clotted for serum and centrifuged at 4000g for 5 minutes at 4°C. Serum samples then were aliquoted, and stored at -80°C until were assayed with enzyme-linked immunosorbent assay (ELISA) analysis. The serum levels of Contactin-1 (Cat.No: E-EL-H1498) and Contactin-2 (Cat.No: E-EL-H1499) were measured with commercially available specific human ELISA kits (Elabscience, Houston, Texas, United States). Paced Auditory Serial Addition Test with the 3-second stimulus (PASAT-3) was used as a measure of cognitive performance including information processing speed, working memory and sustained attention

Inclusion Criteria:

• definite diagnosis of RRMS according to the McDonalds criteria,
• 18 years or older,
• EDSS levels of 1.0 - 5.5, EDSS "pyramidal functions" sub score ≥2,
• who have not had an attack in the last 3 months,
• who were patients who did not receive steroid treatment for the last 3 months.

Exclusion Criteria:

• orthopedic, cardiopulmonary, or systemic problems that prevent participation in exercises,
• pregnancy,
• started immunomodulatory treatment in the last 6 months,
• participated in resistance training 3 months before inclusion in the study.

The study will be carried out on individuals with MS followed in the Neurology Clinic of Fırat University Hospital.