Exercise Training Effects on Muscle Function in Adults With Mitochondrial Myopathy

Official title

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

Overview

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.

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.

Interventions

• 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

Primary outcome measures

• Muscle mitochondrial respiration [Time frame: 24-72 hours after final training session]
• Muscle mitochondrial reactive oxygen species (ROS) production [Time frame: 24-72 hours after final training session]

Secondary outcome measures (4)

• Muscle strength and endurance [Time frame: At first, fifth and tenth training session]
• Muscle structure and neuromuscular junction morphology [Time frame: 24-72 hours after final training session]
• Muscle integrated stress responses, growth and metabolic signaling [Time frame: 24-72 hours after final training session]
• Body and leg composition [Time frame: Baseline and 24-72 hours after final training session]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

Denmark · 1 center

• University of Copenhagen, Dept of Biomedical Sciences — Copenhagen

Publications

• Saltin B, Nazar K, Costill DL, Stein E, Jansson E, Essen B, Gollnick D. The nature of the training response; peripheral and central adaptations of one-legged exercise. Acta Physiol Scand. 1976 Mar;96(3):289-305. doi: 10.1111/j.1748-1716.1976.tb10200.x. PMID 132082
• 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 JL, Blakely EL, Schaefer AM, He L, Wyrick P, Haller RG, Taylor RW, Turnbull DM, Taivassalo T. Resistance training in patients with single, large-scale deletions of mitochondrial DNA. Brain. 2008 Nov;131(Pt 11):2832-40. doi: 10.1093/brain/awn252. PMID 18984605
• MacInnis MJ, Zacharewicz E, Martin BJ, Haikalis ME, Skelly LE, Tarnopolsky MA, Murphy RM, Gibala MJ. Superior mitochondrial adaptations in human skeletal muscle after interval compared to continuous single-leg cycling matched for total work. J Physiol. 2017 May 1;595(9):2955-2968. doi: 10.1113/JP272570. Epub 2016 Aug 3. PMID 27396440
• La Morgia C, Maresca A, Caporali L, Valentino ML, Carelli V. Mitochondrial diseases in adults. J Intern Med. 2020 Jun;287(6):592-608. doi: 10.1111/joim.13064. PMID 32463135
• Jeppesen TD, Schwartz M, Olsen DB, Wibrand F, Krag T, Duno M, Hauerslev S, Vissing J. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain. 2006 Dec;129(Pt 12):3402-12. doi: 10.1093/brain/awl149. Epub 2006 Jun 30. PMID 16815877
• Damas F, Phillips SM, Libardi CA, Vechin FC, Lixandrao ME, Jannig PR, Costa LA, Bacurau AV, Snijders T, Parise G, Tricoli V, Roschel H, Ugrinowitsch C. Resistance training-induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage. J Physiol. 2016 Sep 15;594(18):5209-22. doi: 10.1113/JP272472. Epub 2016 Jul 9. PMID 27219125
• Cejudo P, Bautista J, Montemayor T, Villagomez R, Jimenez L, Ortega F, Campos Y, Sanchez H, Arenas J. Exercise training in mitochondrial myopathy: a randomized controlled trial. Muscle Nerve. 2005 Sep;32(3):342-50. doi: 10.1002/mus.20368. PMID 15962332

Identifiers

NCT: NCT07450690 · H-25048935

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗