Exercise Study Testing Enhanced Energetics of Muscle Mitochondria in CKD
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 12/14/2018 |
| Start Date: | April 2019 |
| End Date: | April 2022 |
| Contact: | Baback Roshanravan, MD MS MSPH |
| Email: | broshanr@ucdavis.edu |
| Phone: | 5307540893 |
A Randomized, Controlled Trial of Combined Aerobic and Resistance Exercise on Muscle Mitochondrial Function and Metabolism
Skeletal muscle dysfunction (sarcopenia) is an under-recognized target organ complication of
CKD with substantial adverse clinical consequences of disability, hospitalization, and death.
Sarcopenia in this proposal is defined by impaired metabolism and physical function
associated with decreased skeletal muscle mass or function. Skeletal muscle tissue relies on
mitochondria to efficiently utilize oxygen to generate ATP. Impaired mitochondrial energetics
is a central mechanism of sarcopenia in CKD. The investigators propose a series of studies
designed to shed light on the pathophysiology of sarcopenia in persons with CKD not treated
with dialysis. Investigators will conduct a randomized-controlled intervention trial of
combined resistance training and aerobic exercise vs. health education to assess changes in
skeletal muscle mitochondrial function, metabolism and physical function. Investigators
hypothesize that exercise improves mitochondrial function and physical function in persons
with CKD. If successful, these experiments will identify novel pathophysiologic mechanisms
for CKD-associated sarcopenia. The proposed study will provide useful insight into benefits
associated with exercise among patients with CKD and investigate mechanisms associated with
improved metabolism, muscle function and physical function in population.
CKD with substantial adverse clinical consequences of disability, hospitalization, and death.
Sarcopenia in this proposal is defined by impaired metabolism and physical function
associated with decreased skeletal muscle mass or function. Skeletal muscle tissue relies on
mitochondria to efficiently utilize oxygen to generate ATP. Impaired mitochondrial energetics
is a central mechanism of sarcopenia in CKD. The investigators propose a series of studies
designed to shed light on the pathophysiology of sarcopenia in persons with CKD not treated
with dialysis. Investigators will conduct a randomized-controlled intervention trial of
combined resistance training and aerobic exercise vs. health education to assess changes in
skeletal muscle mitochondrial function, metabolism and physical function. Investigators
hypothesize that exercise improves mitochondrial function and physical function in persons
with CKD. If successful, these experiments will identify novel pathophysiologic mechanisms
for CKD-associated sarcopenia. The proposed study will provide useful insight into benefits
associated with exercise among patients with CKD and investigate mechanisms associated with
improved metabolism, muscle function and physical function in population.
Sarcopenia is a common complication of chronic kidney disease. Sarcopenia is defined by
decreased muscle mass or function and is central to the frailty phenotype that is associated
disability, hospitalization, and death. Sarcopenia is a common and devastating complication
of chronic kidney disease (CKD). The investigators and others have demonstrated a high
prevalence of physical frailty among CKD patients not treated with dialysis. Furthermore the
investigators have demonstrated greater than 30% impairment in lower extremity physical
performance measures in persons with CKD compared with predicted values. The aging
demographic among CKD patients will result in a substantial U.S. public health burden
attributable to sarcopenia. In the year 2000, direct healthcare costs attributable to
sarcopenia in the U.S. were18.5 billion.
Sarcopenia is associated with adverse health-related outcomes. Sarcopenia in older adults is
consistently linked with decreased physical functioning, disability, falls, hospitalization,
and mortality. Impaired lower extremity physical performance, as measured by objective
testing, is associated with all-cause mortality in CKD patients not treated with dialysis and
that these associations are stronger in magnitude than those for traditional risk factors.
Skeletal muscle is major site of peripheral glucose utilization ameliorating oxidative stress
and endothelial injury associated with acute post-prandial hyperglycemia. Through these
mechanisms sarcopenia may contribute to metabolic disturbances of insulin resistance,
oxidative stress, and endothelial dysfunction leading to cardiovascular disease.
Mitochondrial dysfunction is central to skeletal muscle dysfunction. Skeletal muscle
mitochondria are necessary for the efficient generation of energy (ATP) from oxygen and
normal lipid metabolism. Under normal conditions, muscle efficiently utilizes the majority of
supplied oxygen such that only 0.2% of mitochondrial oxygen is shuttled into reactive
oxidative species (ROS). Under pathologic situations there is uncoupling of oxygen
consumption and ATP generation resulting in increased oxygen consumption and decreased ATP
production in a process leading to increased ROS and oxidative stress. Uncoupling of oxygen
and ATP generation directly affects skeletal muscle function. Decreased efficiency of ATP
generation has been linked to decreased muscle strength and more recently associated with
decreased gait speed in older adults.
Magnetic resonance spectroscopy and optical spectroscopy (MRS/OS) provide novel, non-invasive
and real-time insight into human skeletal muscle mitochondrial function. MRS/OS is a novel
technique that measures maximal mitochondrial ATP production in-vivo following acute bouts of
ischemia induced by exercise using phosphorous MRS (31P MRS). The rate of recovery of
phosphocreatinine after cessation of exercise is used to characterize the rate of aerobic
mitochondrial ATP resynthesis above that of basal anaerobic glycolytic ATP production. By
combining this technique with optical spectroscopy post-exercise measuring the transport of
oxygen from hemoglobin to myoglobin within the muscle the investigators are able to
accurately determine the ratio of coupling efficiency between of ATP generation per unit of
oxygen consumption. Skeletal muscle mitochondrial dysfunction measured by ATP generating
capacity and coupling efficiency has been associated with processes of aging and insulin
resistance. Furthermore studies in healthy subjects have shown that muscle performance and
fatigue are linked to the ability to resynthesize ATP rather than lactate concentration.
Preliminary MRS/OS findings suggest profoundly altered mitochondrial function in CKD
patients. Previous experimental studies suggest that uremia in dialysis patients affects
skeletal muscle structure and mitochondrial function. Oxidative damage is highly prevalent in
CKD, evidenced by increased biomarkers of oxidative stress and changes in glutathione, an
important antioxidant. Prior small studies in non-diabetic CKD patients suggest impairment of
ex-vivo mitochondrial function by reductions in mitochondrial enzyme activity. Based on these
findings investigators used novel, non-invasive, functional MRS/OS assay to characterize
in-vivo mitochondrial function. Preliminary findings in non-diabetic CKD patients indicate
markedly reduced ATP to oxygen ratio compared to controls. This finding suggests altered
mitochondrial energetics as a candidate central mechanism linking metabolic derangements and
impaired physical function in CKD, and motivate the hypothesis that mitochondrial dysfunction
is associated with oxidative stress, insulin resistance and impaired physical functioning in
CKD.
Exercise may ameliorate mitochondrial dysfunction, insulin resistance and physical
functioning in CKD. Studies of exercise in non-CKD patients with diabetes and insulin
resistance have demonstrated exercise-induced improvements in mitochondrial biogenesis linked
to improved insulin sensitivity as well as decreased mitochondrial oxidative stress. Animal
studies suggest that exercise stimulates autophagy resulting in removal of defective and
inefficient mitochondrial leading to a healthy mitochondrial network and improved insulin
sensitivity.The primary goal of this study is to investigate the impact of combined
resistance and aerobic exercise on skeletal muscle dysfunction. Given the investigator's
preliminary data demonstrating strong association of sarcopenia and mortality in CKD,
effective interventions that can impact physical function are urgently needed to improve
patient health outcomes.
decreased muscle mass or function and is central to the frailty phenotype that is associated
disability, hospitalization, and death. Sarcopenia is a common and devastating complication
of chronic kidney disease (CKD). The investigators and others have demonstrated a high
prevalence of physical frailty among CKD patients not treated with dialysis. Furthermore the
investigators have demonstrated greater than 30% impairment in lower extremity physical
performance measures in persons with CKD compared with predicted values. The aging
demographic among CKD patients will result in a substantial U.S. public health burden
attributable to sarcopenia. In the year 2000, direct healthcare costs attributable to
sarcopenia in the U.S. were18.5 billion.
Sarcopenia is associated with adverse health-related outcomes. Sarcopenia in older adults is
consistently linked with decreased physical functioning, disability, falls, hospitalization,
and mortality. Impaired lower extremity physical performance, as measured by objective
testing, is associated with all-cause mortality in CKD patients not treated with dialysis and
that these associations are stronger in magnitude than those for traditional risk factors.
Skeletal muscle is major site of peripheral glucose utilization ameliorating oxidative stress
and endothelial injury associated with acute post-prandial hyperglycemia. Through these
mechanisms sarcopenia may contribute to metabolic disturbances of insulin resistance,
oxidative stress, and endothelial dysfunction leading to cardiovascular disease.
Mitochondrial dysfunction is central to skeletal muscle dysfunction. Skeletal muscle
mitochondria are necessary for the efficient generation of energy (ATP) from oxygen and
normal lipid metabolism. Under normal conditions, muscle efficiently utilizes the majority of
supplied oxygen such that only 0.2% of mitochondrial oxygen is shuttled into reactive
oxidative species (ROS). Under pathologic situations there is uncoupling of oxygen
consumption and ATP generation resulting in increased oxygen consumption and decreased ATP
production in a process leading to increased ROS and oxidative stress. Uncoupling of oxygen
and ATP generation directly affects skeletal muscle function. Decreased efficiency of ATP
generation has been linked to decreased muscle strength and more recently associated with
decreased gait speed in older adults.
Magnetic resonance spectroscopy and optical spectroscopy (MRS/OS) provide novel, non-invasive
and real-time insight into human skeletal muscle mitochondrial function. MRS/OS is a novel
technique that measures maximal mitochondrial ATP production in-vivo following acute bouts of
ischemia induced by exercise using phosphorous MRS (31P MRS). The rate of recovery of
phosphocreatinine after cessation of exercise is used to characterize the rate of aerobic
mitochondrial ATP resynthesis above that of basal anaerobic glycolytic ATP production. By
combining this technique with optical spectroscopy post-exercise measuring the transport of
oxygen from hemoglobin to myoglobin within the muscle the investigators are able to
accurately determine the ratio of coupling efficiency between of ATP generation per unit of
oxygen consumption. Skeletal muscle mitochondrial dysfunction measured by ATP generating
capacity and coupling efficiency has been associated with processes of aging and insulin
resistance. Furthermore studies in healthy subjects have shown that muscle performance and
fatigue are linked to the ability to resynthesize ATP rather than lactate concentration.
Preliminary MRS/OS findings suggest profoundly altered mitochondrial function in CKD
patients. Previous experimental studies suggest that uremia in dialysis patients affects
skeletal muscle structure and mitochondrial function. Oxidative damage is highly prevalent in
CKD, evidenced by increased biomarkers of oxidative stress and changes in glutathione, an
important antioxidant. Prior small studies in non-diabetic CKD patients suggest impairment of
ex-vivo mitochondrial function by reductions in mitochondrial enzyme activity. Based on these
findings investigators used novel, non-invasive, functional MRS/OS assay to characterize
in-vivo mitochondrial function. Preliminary findings in non-diabetic CKD patients indicate
markedly reduced ATP to oxygen ratio compared to controls. This finding suggests altered
mitochondrial energetics as a candidate central mechanism linking metabolic derangements and
impaired physical function in CKD, and motivate the hypothesis that mitochondrial dysfunction
is associated with oxidative stress, insulin resistance and impaired physical functioning in
CKD.
Exercise may ameliorate mitochondrial dysfunction, insulin resistance and physical
functioning in CKD. Studies of exercise in non-CKD patients with diabetes and insulin
resistance have demonstrated exercise-induced improvements in mitochondrial biogenesis linked
to improved insulin sensitivity as well as decreased mitochondrial oxidative stress. Animal
studies suggest that exercise stimulates autophagy resulting in removal of defective and
inefficient mitochondrial leading to a healthy mitochondrial network and improved insulin
sensitivity.The primary goal of this study is to investigate the impact of combined
resistance and aerobic exercise on skeletal muscle dysfunction. Given the investigator's
preliminary data demonstrating strong association of sarcopenia and mortality in CKD,
effective interventions that can impact physical function are urgently needed to improve
patient health outcomes.
Inclusion Criteria:
- Moderate-severe CKD determined by estimated glomerular filtration rate (eGFR)
<50ml/min per 1.73m2
- No history chronic treatment with dialysis.
- Age 18 years old to 75 years
- Sedentary defined as self-reporting no more than 1 day per week of regular
(structured) endurance exercise (EE) [e.g., brisk walking, jogging/running, cycling,
elliptical, or swimming activity that results in feelings of increased heart rate or
rapid breathing (EE), and/or sweating] or resistance exercise (RE) (resulting in
muscular fatigue) lasting no more than 60 minutes in the past year
Exclusion Criteria:
- Current or previous transplantation
- Current pregnancy
- Wheelchair dependence
- Oxygen dependent Chronic obstructive pulmonary disease (COPD)
- Shortness of breath after walking <100 steps on flat surface
- Weight >300 pounds
- HIV infection or hepatitis viral infection
- Liver cirrhosis
- Active malignant cancer other than non-melanomatous skin cancer
- Drugs that alter mitochondrial function:
- muscle relaxants (methocarbamol, baclofen, tizanidine, carisoprodol,
cyclobenzaprine)
- oral steroids (Equivalent of 10mg or more of prednisone daily)
- anti-viral medications (tenofovir, zalcitabine, didanosine, stavudine,
lamivudine, zidovudine, abacavir, adefovir, interferon, ribavirin, efavirenz,
dasabuvir, ombitasvir)
- oral calcineurin inhibitors (Tacrolimus, Cyclosporine)
- Antiepileptic drugs (Phenytoin, phenobarbital, carbamazepine, valproic acid,
oxcarbazepine, ethosuximide, zonisamide, topiramate, and vigabatrin)
- Antipsychotics (haloperidol, thioridazine, risperidone, quetiapine, clozapine,
olanzapine and aripiprazole)
- Drugs- anticoagulants or antiplatelets
- Anticoagulants, any 1 (coumadin, rivaroxaban, apixaban, dabigatran, edoxaban)
- Antiplatelets, any 2 (aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel,
ticagrelor, ticlopidine, vorapaxar)
- Implants that prohibit MRI measurements or trauma involving metal fragments
- Pacemaker
- Vascular stent: bare metal or any recently placed (within 6 months)
- Current substance abuse
- Institutionalization
- Current participation in an interventional trial
- Inability to provide informed consent without a proxy respondent
- Non-English speaking
- Any condition which in the judgement of the clinical investigator places the
participant at risk from participation in the study.
Additional Criteria:
- On chronic dialysis
- Expectation to start dialysis within 6 months.
- Insulin dependent diabetes
- Baseline systolic blood pressure >170 or diastolic blood pressure >100
We found this trial at
1
site
2315 Stockton Blvd
Sacramento, California 95817
Sacramento, California 95817
Principal Investigator: Baback Roshanravan, MD MS
Phone: 530-754-0893
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