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.
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
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
10
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.
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
RECRUITINGfMQ
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.
Time frame: 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
Time frame: Enrollment to end of study at 18 weeks
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Week 1 and Week 12
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