| Outcome Measures: |
Primary: muscle mitochondrial oxidative capacity by 31P MRS, We will use 31P MRS to evaluate the concentration of phospho-creatine (PCr) and other phosphate-energy carrier molecules in limb muscles. After one minute of basal resting measurements, patients will be asked to perform two knee extensions every second against ankle weights 5-10% of the maximal voluntary contraction. The exercise protocol will last 60-90 seconds (a total of 60 knee extensions) followed by 6 minutes of rest. The intensity of the exercise decreases phosphocreatine (PCr) levels with minimal change in muscle pH. Spectra analysis was performed with AMARES from the jMRUI software package. Spectra are used to calculate the relative concentrations of inorganic phosphate (Pi), PCr, and ATP. PCr recovery will be measured through 6min of rest and fit with a monoexponential equation., 16 weeks|Insulin sensitivity (SI) by insulin clamp, Primary endpoint for the hyperinsulinemic euglycemic clamp testing will be insulin sensitivity defined as (glucose disposal rate - concentration of infused glucose)/(insulin concentration at steady state - fasting insulin concentration). Units are mg/min per microunit per milliliter., 16 weeks|total work performed on cycle ergometry VO2, Total work will be obtained by cycle ergometry using standard protocol measuring oxygen uptake starting at 0 watts (W) at 60 rotations per minute (rpm) increasing by 25W every 2 minutes until volitional exhaustion adapting a prior protocol used in CKD patients. The primary measure will be total work completed (Joules)., 16 weeks|muscle work efficiency cycle ergometry, joules/ml Oxygen(VO2 peak), 16 weeks|Walking endurance by 6-minute walk, Meters, 16 weeks|FACIT-F Fatigue (PRO), score on FACIT-F questionnaire, 16 weeks | Secondary: Intermuscular fat by MRI, Percent intermuscular fat., 16 weeks|30 second sit to stand test, number of times patient can get up from sitting position over 30 seconds, 16 weeks|PROMIS Fatigue (PRO), score on NIH PROMIS Fatigue questionnaire, 16 weeks | Other: Muscle mitochondrial respiration from in situ high resolution respirometry of muscle biopsy tissue, We will determine mitochondrial respiration and oxidative stress under different respiratory states including subsaturating and saturating ADP (state 3), using a combination of complex I (glutamate + malate) and complex II (succinate) substrates, state 4 respiration (proton leak in the absence of ADP and the presence of oligomycin), and fully uncoupled respiration using FCCP. The assay for mtH2O2 production is based on the rate of production of the fluorescent molecule, resorufin, when Amplex Red reacts with H2O2 as described. We a priori select mtH2O2 of reverse electron transport (succinate as substrate in the absence of ADP) as our primary endpoint given the evidence that complex I is the predominant source of mtROS during aerobic exercise. Units are pmol/sec., 16 weeks|Inflammatory cytokines. TNF-alpha and IL-6, Inflammatory cytokines. Units pg/ml., 16 weeks
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| Locations: |
University of California Davis Health, Sacramento, California, 95817, United States|Vanderbilt University Medical Center, Nashville, Tennessee, 37232, United States
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