Skeletal Muscle Aging and Responsiveness in Aged People With MS (MS-M3AX)

The purposes of this study are to: 1) compare baseline muscle and cardiovascular health in older individuals (>60 years old) diagnosed with MS to age-matched people without MS, 2) determine muscle and whole body changes to an exercise training program, 3) determine if the muscle in a more affected leg in individuals diagnosed with MS is different from the muscle of a less affected leg, and 4) if or how individuals diagnosed with MS adapt differently than age-matched people without MS to exercise training. Participation in this study will average 1.5 hours per visit, 3 visits per week, for approximately 4 months.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Aging
• Intervention / Treatment: Other: Exercise trial consisting of both cardiovascular and strength training

Detailed Description

Disease-modifying therapies (DMT) are effective in reducing the risk of developing additional debilitating symptoms of multiple sclerosis (MS) and slowing disease progression, leading to better functional mobility outcomes and quality of life. As a result, people with MS (PwMS) are now more likely to maintain independence into their later years. Since older PwMS maintaining independence is a relatively recent phenomenon, there is virtually nothing known about how MS exacerbates the age-related loss of muscle mass and function (i.e., sarcopenia) or how PwMS adapt to interventions, such as exercise, that slow age-related declines. In addition, PwMS are known to be highly heterogeneous in functional ability, fatigue, and other physical factors. The investigators do not yet understand the aging trajectory in PwMS and if current treatment guidelines for aged individuals for overall health, including maintaining muscle mass and function, are effective in aged PwMS.

Aging-related functional declines are thought to be caused by hallmark biological processes that ultimately manifest in physical, mental, and metabolic impairments, which compromise healthspan and quality of life. Exercise is a multipotent treatment with promise to mitigate most aging hallmarks. However, there is substantial variability in how individuals respond to exercise training, which is termed inter-individual response heterogeneity (IRH). Low cardiorespiratory fitness (CRF, VO2max) and low functional muscle quality (fMQ; strength/muscle mass) are multi-system manifestations of the deterioration of the cellular hallmarks of aging, but both CRF and fMQ are modifiable with endurance exercise training (ET) and resistance exercise training (RT). It is yet to be determined how the hallmarks of aging influence IRH. For example, poor responder status could be caused by hallmark deterioration of mitochondrial function, ability to maintain proteostasis, or systemic inflammation.

The investigators are conducting an NIH funded clinical trial that hypothesizes that factors central to aging itself, such as proteostasis, mitochondrial energetics, and inflammation, are contributors to the multidimensional circuitry that determines whether an individual achieves the minimum clinically important difference (MCID) in CRF and/or fMQ with exercise training. The goal of the funded trial is to disentangle the complicated relationships between endogenous and exogenous factors that drive response variation to exercise. To accomplish this goal, investigators will use tissue (muscle and blood) sampling, multi-omics, extensive phenotyping, and multidimensional modeling. For the PHF proposal, investigators will leverage this ongoing clinical trial and enroll aged PwMS into the study. The overall goal of the current proposal is to establish baseline muscle and overall health characteristics, responsiveness to exercise training, and factors that give rise to heterogeneity of symptomology in aged PwMS.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lena Fuentes; Phone Number: 4052717745; Email: lena-fuentes@omrf.org
• Study Contact Backup: Name: Bobbette Miller; Phone Number: 4052714214; Email: bobbette-miller@ou.edu

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • Oklahoma Medical Research Foundation
      • Contact: Lena Fuentes; Phone Number: 4052717745; Email: lena-fuentes@omrf.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Male or female aged 60 or above 2. Free of unmanaged chronic diseases other than multiple sclerosis 3. No structured exercise program (2 or more bouts/wk) within previous 6 months 4. Cognitively capable of providing informed consent 5. Must meet EDSS score between 2 to 5.5 during screening

Exclusion Criteria:

• 1. Neuromuscular or musculoskeletal disorder, other than multiple sclerosis, that would limit the ability to perform the exercise and/or testing bouts.

  2. Cardiopulmonary disorders or reduced breathing capacity

  3. Metabolic diseases including markers of liver disease (ALT > 52 U/dl) and type 2 diabetes (HbA1C ≥ 6.5, fasting blood glucose ≥ 126 mg/dl)

  4. Taking any dose of metformin

  5. Any other disease or disorder that would influence exercise response (e.g., chronic kidney disease, Alzheimer's, current cancer diagnosis or within 2 yr remission, cerebrovascular)

  6. History of Chemotherapy within 5 years

  7. Unchangeable anticoagulant (Coumadin, Pradaxa, etc.) use. To be determined by clinical staff.

  8. Insulin sensitizing/blood glucose lowering (e.g., metformin) or metabolic (GLP1 agonists) drugs.

  9. High dose statin (40 mg and above)

  10. Have a non-correctable visual impairment

  11. Score less than 29 on the Symbol Digit Test

  12. Received Botox for spasticity within the prior 3 months of study participation.

  13. Cannot have any adjustments to Baclofen during study participation.

  13. Unable to commit to ~4 months required to complete the study.

  14. Lidocaine allergy

  15. Tobacco use

  16. Excessive alcohol consumption (3 drinks/d or 7 drinks/wk for females; 4 drinks/day or drinks/wk for males)

  17. BMI greater than 35.0 kg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: People with MS; People with MS, 60 or older

Other: Exercise trial consisting of both cardiovascular and strength training; All participants will receive 12 weeks of combined ET and RT. All exercise is supervised with a certified trainer. All study staff are CPR trained. Progression of volume and intensity will occur during the ramp-up week and into the first week of training. The ramp-up period increases the number of sets, repetitions, and intensity to limit excessive muscle damage, soreness, and fatigue. Full volume training will be achieved by the end of week one and progression thereafter will be based on intensity. Participants will complete 3x/wk ET and 3x/week RT. Both ET and RT will be progressed on an individual level via monitoring of each session with pragmatic increases in cycling wattage, treadmill speed/grade, and weight lifted as needed. At the completion of training there will be a testing week that repeats the battery of testing completed during the wash-in period to determine responder status by the a priori designated MCIDs for CRF and fMQ.; Other Names: strength; endurance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
fMQ	Investigators will determine fMQ from bilateral one-repetition maximum (1RM) knee extension strength / bilateral thigh lean mass via dual-energy x-ray absorptiometry (DXA). Strength testing will be performed with a study trainer and DXA scanning will occur at Oklahoma Children's Hospital OU Health.	Week -3 and Week -2
CRF	Investigators will test CRF on a cycle ergometer using a continuous ramp protocol and ECG monitoring. The study clinician will monitor the ECG during testing while 1-2 other study personnel are administering the test. The ideal ramp for the individual is based on sex, body size, and initial assessments during familiarization	Enrollment to end of study at 18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total and Regional Body Composition	Additional clinical phenotyping includes total and regional body composition scans using a GE Lunar iDXA and insulin resistance by HOMA-IR from fasting blood draws obtained from a study phlebotomist. An Octave biomarker panel will also be evaluated from blood draws.	Week -3 and Week -2
Muscle Biopsy	Investigators will use established methods to assess hallmarks of aging. Investigators will assess proteostasis in skeletal muscle using the final muscle biopsy sample from each leg with tracer-based proteomics. Investigators will use high-resolution respirometry on skeletal muscle mitochondria (Oroboros O2K respirometers) to determine both mitochondrial respiratory function and reactive oxygen species generation.	Week 1 and Week 12 Muscle Biopsy
Skeletal Muscle Phenotyping	For additional skeletal muscle phenotyping, investigators will perform histological analyses of skeletal muscle with immunohistochemical approaches using the well-established methods for cellular morphology, myofiber type distribution and size heterogeneity, fibrosis, vascularization (capillary supply), senescence/DNA damage, the presence of resident stem cells, and inflammatory cells including M1 macrophages10-12. Image analysis will be performed using the automated workflow in MyoVision.	Week 0, 6, and 12
Systemic Inflammation	Systemic inflammation will be assessed in serum samples using the MSD 10-plex cytokine panel. The cytokines tested, GM-CSF, IL-1alpha, IL-5, IL-7, IL-12, IL-15, IL-16, IL-17A, TNF-beta, and VEGF-A each have dynamic detection ranges respectively, 0.16-750 pg/mL, 0.09-278 pg/mL, 0.14-562 pg/mL, 0.12-563 pg/mL, 0.33-2,250 pg/mL, 0.15-525 pg/mL, 2.83-1,870 pg/mL, 0.31-3,650 pg/mL, 0.08-458 pg/mL, and1.12-562 pg/mL. Increased cytokines (high pg/mL) indicates a more active, heightened immune response with low cytokines (low pg/mL) indicating a normal resting immune system state.	Week 1 and Week 12
Muscle Inflammation	Investigators will also assess muscle inflammation in a targeted manner based on the fold change in expression of 3 receptors (TNFα, Fn14, IL-6) and associated intracellular signaling (p-STAT3, NFKB p-p65).	Week 1 and Week 12
Blood Biomarkers	Investigators also evaluate biomarkers in the blood using the Octave biomarker panel, a panel that measures 18 biomarkers to assess disease level in PwMS. Each biomarker generates an overall activity (DA) score from 1.0 to 10.0. Low DA score indicates more controlled, lower inflammation. A high DA score indicates high inflammation.	Week 1 and Week 12
Mobility and Balance	Mobility and balance testing will be accomplished via the well-established short physical performance battery (SPPB). The scale is a minimum score of 0 and maximum score of 12 with higher scores indicating better lower extremity function.	Week -3 and Week -2
Basic Cognitive Function and Balance	Investigators will assess basic cognitive function (reaction time, impulse control, visual processing speed) and balance with the Sway platform (Sway Medical). A score of 100 indicates perfect stability and lower scores indicate instability with the lowest score being 0.	Week -3 and Week -2
Participant's Self Evaluation of Physical, Mental, and Social Health	Investigators will use the validated Patient-Reported Outcomes Measurement Information System (PROMIS) mental health battery to evaluate participant's perspective on physical, mental, and social health. This test uses a T-score metric (typical range of 20-80) with a mean of 50, and a standard deviation of 10, higher scores indicating higher levels of metric measured with a maximum of >70 indicating severe for negative domains like pain, and scores minimum of <55 being within normal limits/absent of negative domain.	Week -3 and Week -2
Depression	Beck Depression Inventory II will be used to assess the presence and severity of depression symptoms within the past 2 weeks. Minimum score is 0 which indicates no presence of depression, and 63 being the highest score indicating the presence of severe depression.	Week -3 and Week -2
Circadian Rhythm	Circadian rhythm will be assessed using the Morningness-Eveningness Questionnaire. Minimum score of 16 indicates evening preference and highest score of 86 indicates morning preference.	Week -3 and Week -2
Sleep Quality	Pittsburgh Sleep Quality Index is a self-reported questionnaire that will be used to evaluate participant's sleep quality. 0 being the lowest score and 21 being the highest, with higher scores indicating poorer sleep quality.	Week -3 and Week -2
Fatigue	Fatigue will be evaluated using the Modified Fatigue Impact Scale (MFIS) questionnaire to rate fatigue in three categories: physical, cognitive, and psychosocial. A total score ranging from 0 to 84, where higher scores indicate greater fatigue impacting daily life.	Week -3 and Week -2
Gait Speed	A 10 Metre Walk Test will be administered to evaluate participant's gait speed and functional mobility. The total time taken to walk 10 meters is recorded, with slower speed indicating fall risks and higher speeds indicating better mobility.	Week -3 and Week -2
Functional Capacity	The 6 Minute Walk Test will be used to evaluate functional capacity, and measures the distance a participant can walk in 6 minutes. Longer distance covered indicates stronger gross functional capacity.	Week -3 and Week -2
Phenotyping Support with Multidimensional Interindividual Response Heterogeneity	To strengthen the phenotyping to support the multidimensional Interindividual Response Heterogeneity circuitry, investigators will use the Oura ring to monitor activity, sleep, mobility, temperature trends, and additional vital signs.	Week 1 through Week 13
Glucose Monitoring	To strengthen the phenotyping to support the multidimensional Interindividual Response Heterogeneity circuitry, subjects will wear a continuous glucose monitor (CGM) for ~7 d durations using the Dexcom G8 at the beginning and end of exercise training.	Week 1 and Week 12
Dietary Intake	Automated Self-Administered 24-Hour (ASA24) Dietary Assessment Tool will be used to evaluate participant's dietary intake.	Week -3 to -2, Week 0, Week 6, and Week 12
Blood Biomarkers	Investigators also evaluate biomarkers in the blood using the Octave biomarker panel, a panel that measures 18 biomarkers to assess disease level in PwMS. To assess inter-tissue communication, investigators will perform plasma EV long and small RNA-Seq, and whole muscle RNA-Seq and ATAC-Seq. All samples will be processed, sequenced, and analyzed.	Week 1 and Week 12

Collaborators and Investigators

• Sponsor: Oklahoma Medical Research Foundation
• Investigators: Principal Investigator: Benjamin F Miller, Ph.D., Oklahoma Medical Research Foundation; Principal Investigator: Gabriel Pardo, Oklahoma Medical Research Foundation

Publications and helpful links

General Publications

• Long DE, Peck BD, Lavin KM, Dungan CM, Kosmac K, Tuggle SC, Bamman MM, Kern PA, Peterson CA. Skeletal muscle properties show collagen organization and immune cell content are associated with resistance exercise response heterogeneity in older persons. J Appl Physiol (1985). 132(6):1432-1447. doi: 10.1152/japplphysiol.00025.2022 (2022).
• Abbott CB, Lawrence MM, Kobak KA, Lopes EBP, Peelor FF 3rd, Donald EJ, Van Remmen H, Griffin TM, Miller BF. A Novel Stable Isotope Approach Demonstrates Surprising Degree of Age-Related Decline in Skeletal Muscle Collagen Proteostasis. Function (Oxf). 2(4):zqab028. doi: 10.1093/function/zqab028 (2021). Erratum in: Function (Oxf). 3(3):zqac016. doi: 10.1093/function/zqac016 (2022).
• Fuqua JD, Lawrence MM, Hettinger ZR, Borowik AK, Brecheen PL, Szczygiel MM, Abbott CB, Peelor FF 3rd, Confides AL, Kinter M, Bodine SC, Dupont-Versteegden EE, Miller BF. Impaired proteostatic mechanisms other than decreased protein synthesis limit old skeletal muscle recovery after disuse atrophy. J Cachexia Sarcopenia Muscle. 14(5):2076-2089. doi: 10.1002/jcsm.13285 (2023).
• Miller B, Hamilton K, Boushel R, Williamson K, Laner V, Gnaiger E, Davis M. Mitochondrial respiration in highly aerobic canines in the non-raced state and after a 1600-km sled dog race. PLoS One. 12(4):e0174874. doi: 10.1371/journal.pone.0174874 (2017).
• Bubak MP, Davidyan A, O'Reilly CL, Mondal SA, Keast J, Doidge SM, Borowik AK, Taylor ME, Volovičeva E, Kinter MT, Britton SL, Koch LG, Stout MB, Lewis TL Jr, Miller BF. Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities. Aging Cell. 23(9):e14235. doi: 10.1111/acel.14235 (2024).
• Graham ZA, Bubak MP, Raymond-Pope CJ, Cutter GR, McAdam JS, Tuggle SC, Siedlik JA, de Sousa LGO, Chappe EJ, Meece K, Kaur A, Ruiz BSR, Bamman SC, Vanselow KM, Perry TW, Acosta-Arreguin JS, Bohmke NJ, Addison GJ, Bowers JM, Wright RL, Fuentes LD, Smith JE, Esser KA, Miller BF, Bodine SC, Bamman MM. Multidimensional Modeling to Maximize Adaptations to eXercise: The M3AX Trial Rationale and Study Design. J Appl Physiol (1985). doi: 10.1152/japplphysiol.00486.2025. Epub ahead of print (2025).
• Roberts BM, Lavin KM, Many GM, Thalacker-Mercer A, Merritt EK, Bickel CS, Mayhew DL, Tuggle SC, Cross JM, Kosek DJ, Petrella JK, Brown CJ, Hunter GR, Windham ST, Allman RM, Bamman MM. Human neuromuscular aging: Sex differences revealed at the myocellular level. Exp Gerontol. 106:116-124. doi: 10.1016/j.exger.2018.02.023 (2018).
• Lee J, Song RJ, Musa Yola I, Shrout TA, Mitchell GF, Vasan RS, Xanthakis V. Association of Estimated Cardiorespiratory Fitness in Midlife With Cardiometabolic Outcomes and Mortality. JAMA Netw Open. 4(10):e2131284. doi: 10.1001/jamanetworkopen.2021.31284 (2021).
• Gaemelke, T., Pedersen, I. S., Dalgas, U. & Hvid, L. G. Sarcopenia in older people with multiple sclerosis: A cross-sectional study. Mult Scler Relat Disord. 93:106190, doi:10.1016/j.msard.2024.106190 (2025).
• Powers SK, Lynch GS, Murphy KT, Reid MB, Zijdewind I. Disease-Induced Skeletal Muscle Atrophy and Fatigue. Med Sci Sports Exerc. 48: 2307-2319, doi:10.1249/MSS.0000000000000975 (2016).
• Naseri A, Nasiri E, Sahraian MA, Daneshvar S, Talebi M. Clinical Features of Late-Onset Multiple Sclerosis: a Systematic Review and Meta-analysis. Mult Scler Relat Disord. 50:102816, doi:10.1016/j.msard.2021.102816 (2021).
• Klistorner S, Barnett M, Parratt JDE, Yiannikas C, Wang C, Wang D, Shieh A, Klistorner A. Evolution of Chronic Lesion Tissue in Relapsing-Remitting Patients With Multiple Sclerosis: An Association With Disease Progression. Neurol Neuroimmunol Neuroinflamm. 12:e200377, doi:10.1212/NXI.0000000000200377 (2025).

Study record dates

Study Major Dates

• Study Start (Estimated): March 6, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 10, 2026
• First Submitted That Met QC Criteria: March 25, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: exercise; muscle; training; metabolism; skeletal muscle; resistance training; cardiovascular training
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Behavior; Multiple Sclerosis; Motor Activity; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Therapeutics; Physical Therapy Modalities; Patient Care; Exercise Therapy; Rehabilitation; Aftercare; Continuity of Patient Care; Physical Conditioning, Human; Exercise; Resistance Training
• Other Study ID Numbers: 25-23-OMRF; 25-23 (Other Grant/Funding Number: Presbyterian Health Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The data will be partially de-identified. IHMC will only have access to the participant's Subject ID, year of birth (and therefore age), and height/weight, which is necessary for normalization of outcomes such as cardiorespiratory fitness (VO2max testing).

Drug and device information, study documents

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