EFFECTS OF AEROBIC AND RESISTANCE TRAINING ON IMMUNE FUNCTION IN MULTIPLE SCLEROSIS (ABIF-MS)

EVALUATION OF THE EFFECTS OF AEROBIC AND RESISTANCE EXERCISES ON THE IMMUNE SYSTEM AND FUNCTIONAL CAPACITY IN MULTIPLE SCLEROSIS

Background: Multiple Sclerosis (MS) is a chronic immune-mediated, inflammatory, and neurodegenerative central nervous system disorder characterized by axonal damage. This damage leads to various debilitating symptoms such as muscle weakness, fatigue, balance loss, and cognitive decline. While reductions in aerobic capacity and muscle strength are secondary manifestations of MS, physical exercise serves as a crucial therapeutic strategy to manage symptoms and optimize functionality.

Rationale: Aerobic exercise exerts anti-inflammatory effects by reducing adipose tissue mass, promoting anti-inflammatory macrophage polarization, and downregulating toll-like receptors. It also modulates the altered T-helper cytokine balance in MS (characterized by elevated proinflammatory cytokines like IL-1, IL-6, IL-17, IFN-γ, TNF-α and decreased anti-inflammatory IL-10), potentially slowing myelin destruction. Concurrently, progressive resistance training (typically at 60%-80% of maximum voluntary contraction) has been shown to improve muscle strength and reduce perceived fatigue in this population. However, data regarding the specific impacts of these exercise modalities on the immune system remain limited.

Objective:The aim of this randomized controlled trial is to investigate and compare the effects of AEROBIC AND STRENGTHENING (RESISTANCE) EXERCISES ON THE IMMUNE SYSTEM PARAMETERS (SPECIFICALLY CYTOKINE PROFILES) AND OVERALL FUNCTIONALITY IN INDIVIDUALS DIAGNOSED WITH MULTIPLE SCLEROSIS.

Study Overview

• Status: Not yet recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Behavioral: Aerobic and Progressive Resistance Exercise Program; Other: Standard Care (in control arm)

Detailed Description

Multiple Sclerosis (MS) is recognized as a chronic immune-mediated, inflammatory, and neurodegenerative disorder of the central nervous system (CNS) characterized by axonal damage that disrupts neural conduction. The neurodegenerative nature of this neurological disease manifests through a wide spectrum of debilitating symptoms, including muscle weakness, fatigue, loss of balance, speech impairment, diplopia, and cognitive decline. These neurological signs and symptoms vary depending on the anatomical location of the lesions.

As an effective rehabilitation strategy for individuals with MS, exercise manages symptoms, restores function, optimizes quality of life, promotes wellness, and encourages participation in activities of daily living. Previous studies have demonstrated that aerobic activity is inversely associated with MS symptoms, exerting protective and potentially restorative effects. Furthermore, growing evidence suggests that exercise can be considered a disease-modifying therapy in MS. Although reductions in aerobic capacity and endurance are not primary clinical features of MS, they frequently develop as secondary manifestations. Therefore, strategies designed to enhance aerobic endurance and capacity, such as aerobic exercise, are highly valuable in MS management. Consequently, aerobic-based exercise interventions are frequently utilized in the therapeutic management of MS to improve aerobic endurance and capacity. Aerobik exercise is a modality designed to stress the cardiovascular system through continuous, rhythmic engagement of large muscle groups (e.g., jogging, walking, swimming, rowing, and cycle ergometry).

The anti-inflammatory effect of aerobic exercise may prevent systemic inflammatory progression. Exercise counteracts inflammation by reducing adipose tissue mass, which promotes the polarization of macrophages toward an anti-inflammatory state, thereby limiting cytokine production. Additionally, the downregulation of toll-like receptors associated with decreased inflammatory monocytes occurs. The inflammatory state is also modulated in response to exercise stimulation by increased levels of skeletal muscle-derived interleukin-6 (IL-6) and the prevention of sustained cytokine release associated with obesity. Cytokines, critical components of MS pathophysiology, are protein hormones that regulate communication between the innate and adaptive branches of the immune system. In healthy populations, a homeostatic balance exists among T-helper cytokines; however, this balance is altered in MS, reflecting increased proinflammatory cytokines (IL-1, IL-6) and decreased anti-inflammatory cytokines (IL-10). These aberrations can accelerate myelin destruction in the brain and spinal cord. Data regarding the effects of physical activity on the immune system in MS remain limited. Cytokines, the primary focus of exercise-based MS studies, encompass a spectrum of proinflammatory cytokines, including IL-1, IL-2, IL-6, IL-17, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). Most of these cytokines are well-documented contributors to MS pathogenesis.

Recently, there has been a growing interest in resistance exercise training. Resistance training studies in individuals with MS have reported improvements in leg strength, reductions in perceived fatigue, and increases in muscle power. Resistance training protocols in this population have generally been of low-to-moderate intensity, typically utilizing progressive resistance exercise ranging from 60% to 80% of the maximum voluntary contraction.

The aim of this study is to conduct a randomized controlled trial to investigate the EFFECTS OF AEROBIC AND STRENGTHENING EXERCISES ON THE IMMUNE SYSTEM AND FUNCTIONALITY IN INDIVIDUALS DIAGNOSED WITH MULTIPLE SCLEROSIS.

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: berna beren yıldırımoğlu, specialist physiotherapist; Phone Number: +905550823309; Email: calppberna@hotmail.com

Study Locations

• Turkey (Türkiye)
  • Ipekyolu
    • Van, Ipekyolu, Turkey (Türkiye), 65100
      • Van Regional Training and Research Hospital
      • Contact: VAN REGIONAL TRAINING AND RESEARCH HOSPITAL REGIONAL TRAINING AND RESEARCH HOSPITAL; Phone Number: +905555798488; Email: dr_m_okay@hotmail.com
      • Contact: muhammed örün, specialist; Phone Number: +905555798488; Email: dr_m_okay@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Diagnosed with Relapsing-Remitting Multiple Sclerosis (RRMS). Aged between 19 and 45 years. Expanded Disability Status Scale (EDSS) score between 0.5 and 3.5. Not currently receiving steroid therapy (or having no recent corticosteroid treatment within the specified washout period).

Exclusion Criteria:

• Having a high baseline level of physical activity.

Experiencing an acute MS relapse or having a history of a relapse within the past 3 months.

Presence of any orthopedic or bone pathology that would prevent participation in the exercise program.

Concomitant diagnosis of any known neuromuscular or immunological disease other than MS.

Initiating immunomodulatory therapy within the last 6 months.

Presence of visual involvement or symptomatic diplopia.

High-grade lower extremity spasticity, defined as a Modified Ashworth Scale (MAS) score of 3 or 4.

Abnormal white blood cell (WBC) count outside the normal reference range of 4,000-10,000 cells/µL.

Presence of any severe cardiopulmonary condition that would contraindicate or prevent participation in physical exercise.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MS Exercise group; Participants diagnosed with Multiple Sclerosis who will perform a structured exercise program consisting of both aerobic training and progressive strengthening (resistance) exercises.	Behavioral: Aerobic and Progressive Resistance Exercise Program; A structured, supervised exercise program consisting of both aerobic and progressive strengthening (resistance) exercises. Aerobic exercises will include continuous, rhythmic activities involving large muscle groups (e.g., cycle ergometry, walking). Progressive resistance training will target major muscle groups, typically utilizing an intensity ranging from 60% to 80% of the maximum voluntary contraction (MVC). The duration, frequency, and total weeks of the program will be identical for both exercise arms.
Active Comparator: MS Control Group; Participants diagnosed with Multiple Sclerosis who will maintain their current routine medical care and daily life activities without participating in any structured exercise intervention during the study period.	Other: Standard Care (in control arm); Participants in this arm will maintain their current routine medical follow-ups and standard daily life activities. They will not participate in any structured or supervised physical exercise program during the study period.
Experimental: healthy Control Group; Age- and gender-matched healthy individuals who will perform the identical structured exercise program (consisting of aerobic and progressive strengthening exercises) as the MS Exercise Group. This arm will serve to compare the physiological, functional, and immunological (cytokine profiles) responses to exercise between healthy individuals and individuals with MS.	Behavioral: Aerobic and Progressive Resistance Exercise Program; A structured, supervised exercise program consisting of both aerobic and progressive strengthening (resistance) exercises. Aerobic exercises will include continuous, rhythmic activities involving large muscle groups (e.g., cycle ergometry, walking). Progressive resistance training will target major muscle groups, typically utilizing an intensity ranging from 60% to 80% of the maximum voluntary contraction (MVC). The duration, frequency, and total weeks of the program will be identical for both exercise arms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CHANGE FROM BASELINE IN SERUM PROINFLAMMATORY CYTOKINE LEVELS	Circulating serum levels of proinflammatory cytokines-specifically Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-17 (IL-17), Interferon-gamma (IFN-γ), and Tumor Necrosis Factor-alpha (TNF-α)-will be analyzed via Enzyme-Linked Immunosorbent Assay (ELISA) to evaluate the anti-inflammatory effect of the exercise program.	Baseline and Post-intervention (e.g., Week 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CHANGE FROM BASELINE IN FUNCTIONAL EXERCISE CAPACITY	Evaluated using the 6-Minute Walk Test (6MWT). The total distance walked in meters within 6 minutes will be recorded to assess functional exercise capacity and aerobic endurance.	Baseline and Post-intervention (e.g., Week 8)
CHANGE FROM BASELINE IN TIMED 25-FOOT WALK (T25FW)	A MEASURE OF QUANTITATIVE MOBILITY AND LEG FUNCTION BASED ON THE TIME REQUIRED TO WALK 25 FEET AS QUICKLY AS POSSIBLE.	Baseline and Post-intervention (e.g., Week 8)
CHANGE FROM BASELINE IN PERCEIVED FATIGUE IMPACT	Assessed using the Modified Fatigue Impact Scale (MFIS). This 21-item self-report questionnaire evaluates the perceived impact of fatigue on physical, cognitive, and psychosocial functioning. Total scores range from 0 to 84, with higher scores indicating a greater negative impact of fatigue.	Baseline and Post-intervention (e.g., Week 8)
CHANGE FROM BASELINE IN 9-HOLE PEG TEST (9HPT)	A MEASURE OF UPPER EXTREMITY (ARM AND HAND) FUNCTION BASED ON THE TIME REQUIRED TO PLACE AND REMOVE 9 PEGS IN A PEG BOARD.	Baseline and Post-intervention (e.g., Week 8)
CHANGE FROM BASELINE IN PACED AUDITORY SERIAL ADDITION TEST (PASAT-3)	A MEASURE OF COGNITIVE FUNCTION, AUDITORY INFORMATION PROCESSING SPEED, AND CALCULATION ABILITY.	Baseline and Post-intervention (e.g., Week 8)

Collaborators and Investigators

• Sponsor: Seda Saka
• Investigators: Principal Investigator: seda saka, Assoc. Prof. Dr., Haliç University

Publications and helpful links

Helpful Links

• ACUTE EFFECTS OF AEROBIC INTENSITIES ON THE CYTOKINE RESPONSE IN WOMEN WITH T MILD MULTIPLE SCLEROSIS
• INFLUENCE OF COMBINED FUNCTIONAL RESISTANCE AND ENDURANCE EXERCISE OVER 12 WEEKS ON MATRIX METALLOPROTEINASE-2 SERUM CONCENTRATION IN PERSONS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS - A COMMUNITY-BASED RANDOMIZED CONTROLLED TRIAL

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 10, 2026

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Cytokines; Immune System; Physical Functional Performance
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care
• Other Study ID Numbers: KAD-FR-42

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) collected during this trial will not be shared publicly to ensure patient confidentiality and comply with local data protection laws (Personal Data Protection Law / KVKK) and the institutional ethics committee approval. The ethical approval and informed consent forms signed by the participants do not cover the public repository sharing of raw individual data. However, the aggregated summary results and statistical findings will be made available through peer-reviewed publications.

Study Data/Documents

1. Study Protocol
   Information identifier: Study Protocol and SAP
   Information comments: Available after publication.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No