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Principal Investigator: Jorge Luis Gamboa
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $623,768
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
End-stage renal disease (ESRD), the final stage of chronic kidney disease (CKD), requires renal
replacement therapy such as hemodialysis. Every year more than 100,000 individuals start hemodialysis.
Patients undergoing hemodialysis are at increased risk of frailty and sarcopenia. Frailty is a multisystem
impairment associated with vulnerability to stressors, and it is characterized by the presence of unintentional
weight loss, self-reported exhaustion or fatigue, measured muscle weakness, slow walking speed, and low
physical activity. Sarcopenia, defined as a reduction of muscle mass and/or muscle strength, is one of the
components of the frailty phenotype. In the general population, physical exercise prevents the loss of muscle
mass and improves frailty status. In patients with ESRD, however, exercise is not as effective as in the general
population. Mitochondria are essential for proper muscle function, and recent studies suggest that
mitochondrial dysfunction contributes to the reduction in muscle mass. We and others have found that
mitochondrial abnormalities and decreased mitochondrial content are present in patients with ESRD. The
number of mitochondria depends on the balance between biogenesis (generation of new mitochondria) and
mitophagy (degradation of mitochondria). Physical exercise improves mitochondrial function and increases the
mitochondrial number in skeletal muscle in the general population. But the benefits of exercise on
mitochondrial function in patients with ESRD have not been studied.
In this study, we will evaluate the overarching hypothesis that mitochondrial dysfunction hinders the
beneficial effects of exercise in patients with ESRD. Thus, in Specific Aim 1, we will test the hypothesis
that Coenzyme Q10, a mitochondrial-targeted therapy, improves muscle adaptation to exercise training in
patients with ESRD. For this aim, patients with ESRD will be enrolled in a 12-week exercise program or in an
observational group. Patients will also receive either Coenzyme Q10 supplementation or placebo. As a result,
patients will be assigned to four different groups, exercise plus placebo, exercise plus Coenzyme Q10,
observational plus placebo, observational plus Coenzyme Q10. This study design will allow us to evaluate the
individual effect of the interventions and the additive effect of the interventions. We anticipate that the
combination of exercise and Coenzyme Q10 will have an additive effect in improving and mitochondrial function
and physical performance in patients with ESRD. In Specific Aim 2 we will test the hypothesis that the
combination of exercise training and Coenzyme Q10 improves mitochondrial function in patients with ESRD by
increasing mitochondrial respiration and content, and improving mitochondrial dynamics (i.e., remodeling
through fission and fusion). Therefore, we will measure mitochondrial respiration and markers of mitochondrial
biogenesis and dynamics in muscle biopsies within a sub-group of patients from Specific Aim 1. Results from
these studies could affect millions of people with ESRD by improving physical function and their quality of life.
Terms: <Affect><Anaerobic Threshold><Biogenesis><Biopsy><Body Weight decreased><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Trials><Co-Q10><CoQ 10><CoQ10><Coenzyme Q><Coenzyme Q10><Coenzyme Q10 deficiency><DNA copy number><Data><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><ESRD><Electron Transport><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Energy Metabolism - Reference Pathway><Energy Metabolism Pathway><Enrollment><Equilibrium><Exercise><Fatigue><Fiber><Gene Transcription><General Population><General Public><Generations><Genetic Transcription><Health><Hemodialyses><Hemodialysis><Home><Impairment><Individual><Infrastructure><Interval training><Intervention><Intervention Strategies><Investigation><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Replacement Therapy><Lack of Energy><MR Spectroscopy><Magnetic Resonance Spectroscopy><Maintenance><Measures><Metabolic><Mitochondria><Mitochondrial DNA><Morbidity><Morbidity - disease rate><Muscle><Muscle Atrophy><Muscle Cell Contraction><Muscle Contraction><Muscle Fibers><Muscle Mitochondria><Muscle Tissue><Muscle Weakness><Muscle function><Muscular Atrophy><Muscular Contraction><Muscular Weakness><Myotubes><Nephropathy><Origin of Life><Oxygen Consumption><PPAR gamma><PPAR-g><PPAR-γ><PPARgamma><PPARγ><Patient Self-Report><Patients><Permeability><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Persons><Phenotype><Physical Exercise><Physical Function><Physical Performance><Physical activity><Physiologic><Physiological><Placebos><Population><Proteins><QOL><Quality of life><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Randomized><Renal Disease><Renal Failure><Renal Insufficiency><Renal Replacement Therapy><Reporting><Research Design><Respiration><Rhabdomyocyte><Risk><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sarcosomes><Self-Report><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sham Treatment><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Study Type><Supplementation><System><Testing><Thiazolidinedione Receptor><Time><Training><Training Programs><Transcription><Ubiquinone><Uncontrolled Study><Variant><Variation><Voluntary Muscle><Vulnerable Populations><Walking><Weight Loss><Weight Reduction><adverse consequence><adverse outcome><balance><balance function><body weight loss><chronic kidney disease><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><decreased muscle mass><electron transfer><enroll><exercise capacity><exercise intolerance><exercise program><exercise training><exhaustion><fitness program><frailty><homes><improved><in vivo><intervention effect><interventional strategy><kidney disorder><life style intervention><lifestyle intervention><low muscle mass><mitochondrial><mitochondrial dysfunction><mortality><mtDNA><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle strength><muscle wasting><muscular><novel><participant enrollment><patient enrollment><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><placebo control trial><placebo controlled trial><preservation><prevent><preventing><primary CoQ10 deficiency><primary outcome><randomisation><randomization><randomized, clinical trials><randomly assigned><reduced muscle mass><renal disorder><resistance exercise><resistance training><respiratory><respiratory mechanism><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><responders/nonresponders><response><sarcopenia><sarcopenic><secondary outcome><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sham therapy><social role><standard of care><stressor><study design><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tool><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><ubidecarenone><ubiquinone 50><ubiquinone Q10><vulnerable group><vulnerable individual><vulnerable people><walking pace><walking speed><wt-loss>