Exercise Therapy for Mitochondrial Disease
Recruiting in Palo Alto (17 mi)
Overseen byZuela Zolkipli-Cunningham, MBChB, MRCP
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Children's Hospital of Philadelphia
Must not be taking: Investigational agents
Disqualifiers: Cystic fibrosis, Chronic lung disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This is a multi-aim study, studying the effects of conventional exercise (measured through Cardiopulomary Exercises Testing or an in-bed pedal exercise) and passive exercise through periodic acceleration (pGz). Aim 1 will focus on the differences between primary mitochondrial disease (PMD) patients and healthy volunteers. Aim 2 is an exploratory aim, which will be studying the effects in patients admitted to the Children's Hospital of Philadelphia Pediatric Intensive Care Unit (PICU).
Do I need to stop my current medications to join the trial?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.
What data supports the effectiveness of the treatment Conventional Exercise, Periodic Acceleration (pGz) for mitochondrial disease?
Research shows that aerobic exercise can improve exercise capacity and quality of life in patients with mitochondrial diseases. Studies have found that regular exercise increases the body's ability to use oxygen and enhances muscle function, making it a recommended treatment for these conditions.12345
Is exercise therapy safe for people with mitochondrial disease?
Research shows that aerobic exercise is generally safe for people with mitochondrial myopathy, as it improves exercise capacity without harmful changes in muscle or blood markers. However, the safety and benefits can vary depending on the specific genetic mutation, so it's important to have medical supervision.23467
How does the treatment 'Exercise Therapy for Mitochondrial Disease' differ from other treatments for this condition?
This treatment is unique because it combines conventional exercise with periodic acceleration (pGz), which may enhance mitochondrial function by increasing the levels of PGC-1alpha, a protein that promotes the creation of new mitochondria. Unlike other treatments, this approach aims to improve energy production and delay disease progression through physical activity, which has shown protective effects in animal models.378910
Eligibility Criteria
This trial is for males and females aged 10-60 with genetically confirmed mitochondrial myopathy, able to perform clinical exercise tests, and can follow study procedures. It excludes pregnant women, those allergic to Lumason®, individuals with severe diseases or conditions that prevent safe participation, recent investigational drug users, non-ambulatory persons, and certain government employees.Inclusion Criteria
My parents or guardians have agreed to my participation in this study.
I can walk and complete basic exercise tests.
I am between 10 and 60 years old and at least 135 cm tall.
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Exclusion Criteria
Pregnant or lactating females
Cognitive impairment that may preclude ability to comply with study procedures
Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures
See 27 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Intervention
Participants undergo various interventions including CPET, pGz administration through a bed or recliner, and pGz through a Gentle Jogger. Blood draws, vascular ultrasounds, and MRIs are conducted before and after interventions.
3 visits for Aim 1, 2 visits for Aim 2
3 visits (in-person) for Aim 1, 2 visits (in-person) for Aim 2
Follow-up
Participants are monitored for safety and effectiveness after interventions, including measurements of oxygen consumption, heart rate, and other physiological markers.
4 weeks
Treatment Details
Interventions
- Conventional Exercise (Behavioural Intervention)
- Periodic Acceleration (pGz) (Procedure)
Trial OverviewThe study examines the effects of conventional (Cardiopulmonary Exercise Testing or pedal exercise) versus passive exercises (pGz Bed) on patients with primary mitochondrial disease compared to healthy volunteers. Part of the research includes critically ill children in a hospital's intensive care unit.
Participant Groups
3Treatment groups
Experimental Treatment
Group I: Aim 2: PICU PatientsExperimental Treatment3 Interventions
All participants in Aim 2 will have the interventions/study visits occur in the same order: Exercise Pedal and Gentle Jogger
Group II: Aim 1: Primary Mitochondrial Disease PatientsExperimental Treatment4 Interventions
The participant has the interventions/study visits occur in a random order:
CPET pGz administration through pGz Bed pGz administration through Gentle Jogger
Group III: Aim 1: Healthy ControlsExperimental Treatment4 Interventions
The participant has the interventions/study visits occur in a random order:
pGz administration through Gentle Jogger CPET pGz administration through pGz Bed
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital of PhiladelphiaPhiladelphia, PA
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Who Is Running the Clinical Trial?
Children's Hospital of PhiladelphiaLead Sponsor
United States Department of DefenseCollaborator
References
Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. [2019]At present there are limited therapeutic interventions for patients with mitochondrial myopathies. Exercise training has been suggested as an approach to improve physical capacity and quality of life but it is uncertain whether it offers a safe and effective treatment for patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. The objectives of this study were to assess the effects of exercise training and detraining in eight patients with single, large-scale mtDNA deletions to determine: (i) the efficacy and safety of endurance training (14 weeks) in this patient population; (ii) to determine the effect of more prolonged (total of 28 weeks) exercise training upon muscle and cardiovascular function and (iii) to evaluate the effect of discontinued training (14 weeks) upon muscle and cardiovascular function. Our results show that: (i) 14 weeks of exercise training significantly improved tolerance of submaximal exercise and peak capacity for work, oxygen utilization and skeletal muscle oxygen extraction with no change in the level of deleted mtDNA; (ii) continued training for an additional 14 weeks maintained these beneficial adaptations; (iii) the cessation of training (detraining) resulted in loss of physiological adaptation to baseline capacity with no overall change in mutation load. Patients' self assessment of quality of life as measured by the SF-36 questionnaire improved with training and declined with detraining. Whilst our findings of beneficial effects of training on physiological outcome and quality of life without increases in the percentage of deleted mtDNA are encouraging, we did not observe changes in mtDNA copy number. Therefore there remains a need for longer term studies to confirm that endurance exercise is a safe and effective treatment for patients with mitochondrial myopathies. The effects of detraining clearly implicate physical inactivity as an important mechanism in reducing exercise capacity and quality of life in patients with mitochondrial myopathy.
Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. [2022]Exercise intolerance is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still unsettled whether exercise training is safe and beneficial for patients with MM. To address this, we studied the effect of 12 weeks cycle training on exercise capacity, quality of life and underlying molecular and cellular events in five patients with single large-scale deletions, one with a microdeletion and 14 with point mutations of mitochondrial DNA (mtDNA), and 13 healthy subjects. Each training session lasted 30 min, and was performed at an intensity of 70% of VO2max (maximal oxygen uptake). Each subject performed 50 training sessions in 12 weeks. All subjects were evaluated before and after training, and 13 MM patients were studied after 8 weeks of deconditioning. Evaluation included VO2max and mutation load and mtDNA quantity, mitochondrial enzymatic activity, and number of centrally nucleated, apoptotic, ragged red and cytochrome oxidase (COX)-negative fibres in muscle biopsies from the quadriceps muscle. After 12 weeks of training, VO2max and muscle citrate synthase increased in MM (26 and 67%) and healthy (17 and 65%) subjects, while mtDNA quantity in muscle only increased in the MM patients (81%). In the MM patients, training did not change mtDNA mutation load in muscle, mitochondrial enzyme complex activities, muscle morphology and plasma creatine kinase. After deconditioning, VO2max and citrate synthase activity returned to values before training, while muscle mtDNA mutation load decreased. These findings show that aerobic training efficiently improves oxidative capacity in MM patients. Based on unchanged levels of mutant load in muscle, morphological findings on muscle biopsy and plasma creatine kinase levels during training, the treatment appears to be safe. Regular, supervised aerobic exercise is therefore recommended in MM patients with the studied mutations.
Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases. [2022]Fatigue and exercise intolerance are common symptoms of mitochondrial diseases, but difficult to be clinically assessed. New methods to quantify these rather common complaints are strongly needed in the clinical practice. Coenzyme Q10 administration and aerobic exercise may improve exercise intolerance, but more definite studies are still pending. Herein, we have revised "how to measure" and "how to treat" these symptoms of mitochondrial patients. Subsequently, we reviewed the clinical data of the 1164 confirmed mitochondrial patients present in the Italian nation-wide database of mitochondrial disease, with special regard to exercise intolerance. We observed that more of 20% of mitochondrial patients complain of exercise intolerance. This symptom seems to be frequently associated with specific patient groups and/or genotypes. Ragged red fibers and COX-negative fibers are more often present in subjects with exercise intolerance, whereas lactate levels could not predict this symptom. Multicenter efforts are strongly needed for rare disorders such as mitochondrial diseases, and may represent the basis for more rigorous longitudinal studies.
Health Benefits of an Innovative Exercise Program for Mitochondrial Disorders. [2019]We determined the effects of an innovative 8-wk exercise intervention (aerobic, resistance, and inspiratory muscle training) for patients with mitochondrial disease.
Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. [2019]Aerobic training has been shown to increase work and oxidative capacity in patients with mitochondrial myopathies, but the mechanisms underlying improvement are not known. We evaluated physiological (cycle exercise, 31P-MRS), biochemical (enzyme levels), and genetic (proportion of mutant/wild-type genomes) responses to 14 weeks of bicycle exercise training in 10 patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. Training increased peak work and oxidative capacities (20-30%), systemic arteriovenous O2 difference (20%), and 31P-MRS indices of metabolic recovery (35%), consistent with enhanced muscle oxidative phosphorylation. Mitochondrial volume in vastus lateralis biopsies increased significantly (50%) and increases in deficient respiratory chain enzymes were found in patients with Complex I (36%) and Complex IV (25%) defects, whereas decreases occurred in 2 patients with Complex III defects (approximately 20%). These results suggest that the cellular basis of improved oxygen utilization is related to training-induced mitochondrial proliferation likely resulting in increased levels of functional, wild-type mtDNA. However, genetic analysis indicated the proportion of wild-type mtDNA was unchanged (3/9) or fell (6/9), suggesting a trend toward preferential proliferation of mutant genomes. The long-term implications of training-induced increases in mutant relative to wild-type mtDNA, despite positive physiological and biochemical findings, need to be assessed before aerobic training can be proposed as a general treatment option.
Mitochondrial mutations alter endurance exercise response and determinants in mice. [2022]Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been exercise training. Endurance exercise is known to improve mitochondrial function in heathy subjects and reduce risk for secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in PMDs the benefit of endurance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others. Here we investigate the effect of an endurance exercise regimen in mouse models for PMDs harboring distinct mitochondrial mutations. We show that while an mtDNA ND6 mutation in complex I demonstrated improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened the dilated cardiomyopathy. Correlating the gene expression profile of skeletal muscle and heart with the physiologic exercise response identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) structure, and cell cycle regulation as key pathways in the exercise response. This emphasizes the crucial role of mitochondria in determining the exercise capacity and exercise response. Consequently, the benefit of endurance exercise in PMDs strongly depends on the underlying mutation, although our results suggest a general beneficial effect.
Endurance exercise is protective for mice with mitochondrial myopathy. [2022]Defects in the mitochondrial ATP-generating system are one of the most commonly inherited neurological disorders, but they remain without treatment. We have recently shown that modulation of the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) level in skeletal muscle of a mitochondrial myopathy mouse model offers a therapeutic approach. Here we analyzed if endurance exercise, which is known to be associated with an increased PGC-1alpha level in muscle, offers the same beneficial effect. We subjected male and female mice that develop a severe mitochondrial myopathy due to a cytochrome-c oxidase deficiency at 3 mo of age to endurance exercise training and monitored phenotypical and metabolic changes. Sedentary myopathy and wild-type mice were used as controls. Exercise increased PGC-1alpha in muscle, resulting in increased mitochondrial biogenesis, and successfully stimulated residual respiratory capacity in muscle tissue. As a consequence, ATP levels were increased in exercised mice compared with sedentary myopathy animals, which resulted in a delayed onset of the myopathy and a prolonged lifespan of the exercised mice. As an added benefit, endurance exercise induced antioxidant enzymes. The overall protective effect of endurance exercise delayed the onset of the mitochondrial myopathy and increased life expectancy in the mouse model. Thus stimulating residual oxidative phosphorylation function in the affected muscle by inducing mitochondrial biogenesis through endurance exercise might offer a valuable therapeutic intervention for mitochondrial myopathy patients.
ATP, phosphocreatine and lactate in exercising muscle in mitochondrial disease and McArdle's disease. [2019]We studied exercise-induced changes in the adenosine triphosphate (ATP), phosphocreatine (PCr), and lactate levels in the skeletal muscle of mitochondrial patients and patients with McArdle's disease. Needle muscle biopsy specimens for biochemical measurement were obtained before and immediately after maximal short-term bicycle exercise test from 12 patients suffering from autosomal dominant and recessive forms of progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA (adPEO, arPEO, respectively), five patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) 3243 A-->G point mutation, and four patients with McArdle's disease. Muscle ATP and PCr levels at rest or after exercise did not differ significantly from those of the controls in any patient group. In patients with mitochondrial disease, muscle lactate tended to be lower at rest and increase more during exercise than in controls, the most remarkable rise being measured in patients with adPEO with generalized muscle symptoms and in patients with MELAS point mutation. In McArdle patients, the muscle lactate level decreased during exercise. No correlation was found between the muscle ATP and PCr levels and the respiratory chain enzyme activity.
Neuromuscular and Muscle Metabolic Functions in MELAS Before and After Resistance Training: A Case Study. [2020]Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes syndrome (MELAS) is a rare degenerative disease. Recent studies have shown that resistant training (RT) can ameliorate muscular force in mitochondrial diseases. However, the effects of RT in MELAS are unknown. The aim of this case report was to investigate the effects of RT on skeletal muscle and mitochondrial function in a 21-years old patient with MELAS. RT included 12 weeks of RT at 85% of 1 repetition maximum. Body composition (DXA), in vivo mitochondrial respiration capacity (mVO2) utilizing Near-infrared spectroscopy on the right plantar-flexor muscles, maximal voluntary torque (MVC), electrically evoked resting twitch (EET) and maximal voluntary activation (VMA) of the right leg extensors (LE) muscles were measured with the interpolated twitch technique. The participant with MELAS exhibited a marked increase in body mass (1.4 kg) and thigh muscle mass (0.3 kg). After the training period MVC (+5.5 Nm), EET (+2.1 N⋅m) and VMA (+13.1%) were ameliorated. Data of mVO2 revealed negligible changes in the end-exercise mVO2 (0.02 mM min-1), Δ mVO2 (0.09 mM min-1), while there was a marked amelioration in the kinetics of mVO2 (τ mVO2; Δ70.2 s). This is the first report of RT-induced ameliorations on skeletal muscle and mitochondrial function in MELAS. This case study suggests a preserved plasticity in the skeletal muscle of a patient with MELAS. RT appears to be an effective method to increase skeletal muscle function, and this effect is mediated by both neuromuscular and mitochondrial adaptations.
Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. [2014]Muscle is one of the most commonly affected organs in mitochondrial disorders, and the symptoms are often exercise related. The cardiopulmonary exercise test with the determination of lactic acid formation could give supplementary information about the exercise-induced metabolic stress and compensatory mechanisms used in these disorders. The aim of this study was to evaluate the exercise capacity and lactate kinetics related to exercise in subjects with two genetically characterized mitochondrial disorders (multiple mitochondrial DNA deletions with PEO, MELAS) compared with lactate kinetics in subjects with metabolic myopathy (McArdle's disease) and in the healthy controls.