Exercise Training Effects on Muscle Function in Adults With Mitochondrial Myopathy

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.

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.

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