Skeletal Muscle Aging and Responsiveness in Aged People With MS

Overview

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.

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.

Interventions

• 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 intens

Primary outcome measures

• fMQ [Time frame: Week -3 and Week -2]
• CRF [Time frame: Enrollment to end of study at 18 weeks]

Secondary outcome measures (12)

• Total and Regional Body Composition [Time frame: Week -3 and Week -2]
• Muscle Biopsy [Time frame: Week 1 and Week 12 Muscle Biopsy]
• Skeletal Muscle Phenotyping [Time frame: Week 0, 6, and 12]
• Systemic Inflammation [Time frame: Week 1 and Week 12]
• Muscle Inflammation [Time frame: Week 1 and Week 12]
• Blood Biomarkers [Time frame: Week 1 and Week 12]
• Mobility and Balance [Time frame: Week -3 and Week -2]
• Basic Cognitive Function and Balance [Time frame: Week -3 and Week -2]
• Participant's Self Evaluation of Physical, Mental, and Social Health [Time frame: Week -3 and Week -2]
• Depression [Time frame: Week -3 and Week -2]
• Circadian Rhythm [Time frame: Week -3 and Week -2]
• Sleep Quality [Time frame: Week -3 and Week -2]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

United States · 1 center

• Oklahoma Medical Research Foundation — Oklahoma City

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). 2022 Jun 1;132(6):1432-1447. doi: 10.1152/japplphysiol.00025.2022. Epub 2022 Apr 28. PMID 35482328
• 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). 2021 May 10;2(4):zqab028. doi: 10.1093/function/zqab028. eCollection 2021. PMID 34124684
• 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. 2023 Oct;14(5):2076-2089. doi: 10.1002/jcsm.13285. Epub 2023 Jul 14. PMID 37448295
• 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. 2017 Apr 26;12(4):e0174874. doi: 10.1371/journal.pone.0174874. eCollection 2017. PMID 28445477
• Bubak MP, Davidyan A, O'Reilly CL, Mondal SA, Keast J, Doidge SM, Borowik AK, Taylor ME, Voloviceva 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. 2024 Sep;23(9):e14235. doi: 10.1111/acel.14235. Epub 2024 Jun 24. PMID 38923664
• 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 BS, 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 desi PMID 41015496
• 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. 2018 Jun;106:116-124. doi: 10.1016/j.exger.2018.02.023. Epub 2018 Feb 24. PMID 29481967
• 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. 2021 Oct 1;4(10):e2131284. doi: 10.1001/jamanetworkopen.2021.31284. PMID 34714339

Identifiers

NCT: NCT07500727 · 25-23-OMRF · 25-23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗