Exercise Therapy for Mitochondrial Disease

Recruiting in Palo Alto (17 mi)

Overseen by Zuela 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. ^{1 2 3 4 5}

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. ^{2 3 4 6 7}

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. ^{3 7 8 9 10}

Research Team

Zuela Zolkipli-Cunningham, MBChB, MRCP

Principal Investigator

Attending Physician

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.

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

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 Overview The 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

Group I: Aim 2: PICU Patients Experimental Treatment 3 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 Patients Experimental Treatment 4 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 Controls Experimental Treatment 4 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 Nearby Select from list below to view details:

Children's Hospital of Philadelphia Philadelphia, PA

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Patients Recruited

11,400,000+

United States Department of Defense

Collaborator

Trials

940

Patients Recruited

339,000+

Findings from Research

A 14-week endurance training program significantly improved exercise tolerance, peak work capacity, and quality of life in eight patients with mitochondrial myopathies, without affecting the level of deleted mitochondrial DNA (mtDNA).

Detraining for 14 weeks led to a decline in these improvements, highlighting the importance of continued physical activity for maintaining exercise capacity and quality of life in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Taivassalo, T., Gardner, JL., Taylor, RW., et al.[2019]

A 12-week cycle training program significantly improved exercise capacity (VO2max) and muscle enzyme activity in patients with mitochondrial myopathy (MM), indicating that aerobic training can enhance oxidative capacity in these patients.

The training was found to be safe, as it did not alter mtDNA mutation load, muscle morphology, or plasma creatine kinase levels, suggesting that regular supervised aerobic exercise is beneficial for MM patients with specific mitochondrial mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Jeppesen, TD., Schwartz, M., Olsen, DB., et al.[2022]

Over 20% of the 1164 mitochondrial patients studied reported exercise intolerance, indicating that this is a common and significant symptom in this population.

Specific muscle fiber characteristics, such as ragged red fibers and COX-negative fibers, are more frequently found in patients with exercise intolerance, suggesting a potential link between these features and the symptom, while lactate levels were not predictive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases. Mancuso, M., Angelini, C., Bertini, E., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health Benefits of an Innovative Exercise Program for Mitochondrial Disorders. Fiuza-Luces, C., Díez-Bermejo, J., Fernández-DE LA Torre, M., et al.[2019]

A 14-week aerobic training program in 10 patients with mitochondrial myopathies led to significant improvements in physical performance, including a 20-30% increase in peak work and oxidative capacities, indicating enhanced muscle function.

Despite these positive outcomes, genetic analysis revealed that the proportion of functional wild-type mitochondrial DNA did not increase and may have even decreased in some patients, raising concerns about the long-term effects of training on mitochondrial genetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Taivassalo, T., Shoubridge, EA., Chen, J., et al.[2019]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial mutations alter endurance exercise response and determinants in mice. Schaefer, PM., Rathi, K., Butic, A., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endurance exercise is protective for mice with mitochondrial myopathy. Wenz, T., Diaz, F., Hernandez, D., et al.[2022]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATP, phosphocreatine and lactate in exercising muscle in mitochondrial disease and McArdle's disease. Löfberg, M., Lindholm, H., Näveri, H., et al.[2019]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromuscular and Muscle Metabolic Functions in MELAS Before and After Resistance Training: A Case Study. Venturelli, M., Villa, F., Ruzzante, F., et al.[2020]

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. Lindholm, H., Löfberg, M., Somer, H., et al.[2014]

References

1. England pubmed.ncbi.nlm.nih.gov

Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Health Benefits of an Innovative Exercise Program for Mitochondrial Disorders. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Mitochondrial mutations alter endurance exercise response and determinants in mice. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Endurance exercise is protective for mice with mitochondrial myopathy. [2022]

8. England pubmed.ncbi.nlm.nih.gov

ATP, phosphocreatine and lactate in exercising muscle in mitochondrial disease and McArdle's disease. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Neuromuscular and Muscle Metabolic Functions in MELAS Before and After Resistance Training: A Case Study. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. [2014]