Exercise Training Effects on Muscle Function in Adults With Mitochondrial Myopathy (MM-EX)

Deciphering Muscle-Nerve Communication Via Mitochondrial Myopathy Insights: Exploring the Effects of Exercise Training

The goal of this observational study is to learn how exercise training affects molecular processes in skeletal muscle in adults with mitochondrial myopathy, compared with healthy adults.

The main questions it aims to answer are:

• How does exercise training affect mitochondrial activity and energy production pathways in skeletal muscle in people with mitochondrial myopathy?
• How does exercise training affect molecular signals related to muscle growth, stress responses, and muscle-nerve communication in people with mitochondrial myopathy?

Researchers will compare the trained leg to the untrained leg within the same participant, and also compare responses between participants with mitochondrial myopathy and healthy control participants, to see how molecular responses to exercise differ between groups.

The participants will:

• Complete a 3-4-week supervised exercise training program using one leg.
• Undergo muscle biopsies from both the trained and untrained leg.
• Complete basic muscle strength and physical function tests.

Study Overview

• Status: Recruiting
• Conditions: Mitochondrial Diseases; Mitochondrial Myopathy
• Intervention / Treatment: Behavioral: Unilateral high-intensity interval training (HIIT)

Detailed Description

Mitochondrial dysfunction is a central contributor to skeletal muscle weakness, metabolic dysregulation, and reduced physical capacity in mitochondrial myopathies. Defects in mitochondrial oxidative phosphorylation impair energy production and trigger maladaptive cellular stress responses, contributing to progressive muscle deterioration. While structured exercise training has been shown to improve mitochondrial oxidative capacity and functional performance in individuals with mitochondrial myopathy, the cellular and molecular pathways driving these adaptations are not fully defined.

This study employs a within-subject, parallel-group, unilateral exercise training model to examine exercise-induced adaptations in skeletal muscle from adults with mitochondrial myopathy and matched healthy controls. Participants undergo a 3-4-week supervised unilateral aerobic interval training program consisting of 10 sessions, with the trained leg randomized and the contralateral leg serving as an internal untrained control. This design increases statistical power and allows direct comparison of trained versus untrained muscle within the same individual.

Comprehensive phenotyping is conducted before the intervention, including assessments of muscle strength, functional performance, body composition, physical activity, and maximal oxygen uptake. Skeletal muscle biopsies obtained from both legs following the intervention enable detailed evaluation of mitochondrial respiratory function, mitochondrial morphology, neuromuscular junction structure, protein synthesis, signaling pathways, and unbiased multi-omics analyses (proteomics, phosphoproteomics, metabolomics, lipidomics, and transcriptomics).

By integrating physiological, molecular, and structural outcomes, this study seeks to elucidate mechanisms by which exercise training may partially reverse mitochondrial and neuromuscular defects in mitochondrial myopathy and establish exercise as a targeted therapeutic strategy for mitochondrial dysfunction.

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tue L Nielsen, MD; Phone Number: +45 3545 8748; Email: tue.leth.nielsen.01@regionh.dk
• Study Contact Backup: Name: Lykke Sylow, Ass.prof; Email: lykkesylow@sund.ku.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Recruiting
    • University of Copenhagen, Dept of Biomedical Sciences
    • Contact: Lykke Sylow, Ass.prof; Phone Number: 0045 20955250; Email: lykkesylow@sund.ku.dk
    • Contact: Johanne Modvig, M.Sc.; Email: johanne.modvig@sund.ku.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Eligibility criteria for Mitochondrial Myopathy-group:

Inclusion Criteria

• Known mtDNA or nuclear (nDNA) mutations
• Age above or equal to 18 years

Exclusion Criteria:

• Medical conditions which deem the MM patient unfit to complete the study
• Current use of medications known to interact with outcome measures. (see below)
• Pregnancy
• The participant is for any other reason unlikely to complete the study

Inclusion Criteria for healthy controls

• Age above or equal to 18 years

Exclusion Criteria:

• Chronic medical conditions suspected to influence outcome measures
• Frequent use of medicine
• Pregnancy
• The participant is for any other reason unlikely to complete the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mitochondrial Myopathy; Individuals with myopathy caused by mutations in nuclear or mitochondrial DNA	Behavioral: Unilateral high-intensity interval training (HIIT); Participants will undergo ten sessions of HIIT of the leg randomized to the intervention while the inactive leg serves as the control leg
Active Comparator: Healthy controls; Control subjects matched for age, sex and BMI	Behavioral: Unilateral high-intensity interval training (HIIT); Participants will undergo ten sessions of HIIT of the leg randomized to the intervention while the inactive leg serves as the control leg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle mitochondrial respiration	Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized fibers from muscle biopsy samples after either exercise or ususal physical activity	24-72 hours after final training session
Muscle mitochondrial reactive oxygen species (ROS) production	Mitochondrial H2O2 emission rates are measured by high-resolution fluorometry in permeabilized fibers from muscle biopsy samples after either exercise or ususal physical activity	24-72 hours after final training session

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle strength and endurance	Measured by an incremental one-legged test.	At first, fifth and tenth training session
Muscle structure and neuromuscular junction morphology	Measured by histology and TEM from muscle biopsy specimens taken from both trained and untrained leg	24-72 hours after final training session
Muscle integrated stress responses, growth and metabolic signaling	Measured by immunoblotting and Real-Time PCR in muscle biopsies from trained and untrained leg	24-72 hours after final training session
Body and leg composition	as measured by whole-body DXA scanning	Baseline and 24-72 hours after final training session

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global unbiased exploratory metabolomic, lipidomic, proteomic, and microRNA profiling	From trained and untrained muscle biopsy samples from individuals with MM and matched healthy control subjects	24-72 hours after final training session

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Collaborators: Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Saltin, B., Nazar, K., Costill, D.L., Stein, E., Jansson, E., Essén, B., Gollnick, P.D., 1976. The Nature of the Training Response; Peripheral and Central Adaptations to One-Legged Exercise. Acta Physiologica Scandinavica 96, 289-305. https://doi.org/10.1111/j.1748-1716.1976.tb10200.x
• Porcelli, S., Grassi, B., Poole, D.C., Marzorati, M., 2019. Exercise intolerance in patients with mitochondrial myopathies: perfusive and diffusive limitations in the O2 pathway. Current Opinion in Physiology 10, 202-209. https://doi.org/10.1016/j.cophys.2019.05.011
• Murphy, J.L., Blakely, E.L., Schaefer, A.M., He, L., Wyrick, P., Haller, R.G., Taylor, R.W., Turnbull, D.M., Taivassalo, T., 2008. Resistance training in patients with single, large-scale deletions of mitochondrial DNA. Brain 131, 2832-2840. https://doi.org/10.1093/brain/awn252
• MacInnis, M.J., Zacharewicz, E., Martin, B.J., Haikalis, M.E., Skelly, L.E., Tarnopolsky, M.A., Murphy, R.M., Gibala, M.J., 2017b. Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work. J Physiol 595, 2955-2968. https://doi.org/10.1113/JP272570
• La Morgia, C., Maresca, A., Caporali, L., Valentino, M.L., Carelli, V., 2020. Mitochondrial diseases in adults. Journal of Internal Medicine 287, 592-608. https://doi.org/10.1111/joim.13064
• Jeppesen, T.D., Schwartz, M., Olsen, D.B., Wibrand, F., Krag, T., Duno, M., Hauerslev, S., Vissing, J., 2006. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 129, 3402-3412. https://doi.org/10.1093/brain/awl149
• Damas, F., Phillips, S.M., Libardi, C.A., Vechin, F.C., Lixandrão, M.E., Jannig, P.R., Costa, L.A.R., Bacurau, A. V., Snijders, T., Parise, G., Tricoli, V., Roschel, H., Ugrinowitsch, C., 2016. Resistance training-induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage. Journal of Physiology 594, 5209-5222. https://doi.org/10.1113/JP272472
• Cejudo, P., Bautista, J., Montemayor, T., Villagómez, R., Jiménez, L., Ortega, F., Campos, Y., Sánchez, H., Arenas, J., 2005. Exercise training in mitochondrial myopathy: A randomized controlled trial. Muscle Nerve 32, 342-350. https://doi.org/10.1002/mus.20368
• Booth, M., 2000. Assessment of Physical Activity: An International Perspective. Research Quarterly for Exercise and Sport 71, 114-120. https://doi.org/10.1080/02701367.2000.11082794

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2026
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2030

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: March 1, 2026
• First Posted (Actual): March 5, 2026

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 1, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Exercise training; Mitochondrial function; Skeletal Muscle; Neuromuscular Junction; Muscle Plasticity
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Mitochondrial Diseases; Mitochondrial Myopathies
• Other Study ID Numbers: H-25048935

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No