Skeletal Muscle Aging and Responsiveness in Aged People With MS

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.

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

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Automated Self-Administered 24-Hour (ASA24) Dietary Assessment Tool will be used to evaluate participant's dietary intake.

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.