Exercise-mediated Rescue of Mitochondrial Dysfunctions Driving Insulin Resistance

NCT06080594 | Completed

• 1 other identifier: EX-MITO-DYS-IR
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

The overarching aim of this intervention study is to interrogate the interconnection between the muscle mitochondrial adaptations and the changes in muscle insulin sensitivity elicited by exercise training in individuals harbouring pathogenic mitochondrial DNA mutations associated with an insulin-resistant phenotype. In a within-subject parallel-group longitudinal design, participants will undergo an exercise training intervention with one leg, while the contralateral leg will serve as an inactive control. After the exercise intervention, patients will attend an experimental trial including:

• A hyperinsulinemic-euglycemic clamp combined with measurements of femoral artery blood flow and arteriovenous difference of glucose
• Muscle biopsy samples

Conditions

Mitochondrial Myopathies; Mitochondrial Diseases; Mitochondrial Disorders

Keywords

Mitochondrial disease; Muscle metabolism; Insulin resistance; Exercise training; Mitochondrial dysfunction

Outcome Measures

Primary Outcomes (4)

• Skeletal muscle insulin sensitivity

  Insulin-stimulated muscle glucose uptake is determined by the hyperinsulinemic-euglycemic clamp method integrated with measurements of femoral artery blood flow and arteriovenous difference of glucose

  90-150 minutes after initiation of a hyperinsulinemic euglycemic clamp

• Muscle mitochondrial respiration

  Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized fibers from muscle biopsy samples

  Baseline

• Muscle mitochondrial reactive oxygen species (ROS) production

  Mitochondrial H2O2 emission rates are measured by high-resolution fluorometry in permeabilized fibers from muscle biopsy samples

  Baseline

• Muscle mitochondrial proteome

  Mitochondrial proteome signatures are determined by mass spectrometry-based proteomics in muscle biopsy samples

  Baseline

Secondary Outcomes (6)

• Muscle mtDNA heteroplasmy

  Baseline

• Muscle insulin signaling

  Before (baseline) and 150 minutes after initiation of the hyperinsulinemic-euglycemic clamp

• Muscle integrated stress response signaling proteins

  Baseline

• Muscle integrated stress response genes

  Baseline

• Muscle release of FGF21 and GDF15

  Before (baseline) and 0-150 minutes after initiation of the hyperinsulinemic-euglycemic clamp

Other Outcomes (1)

• Leg muscle mass

  Baseline

Study Arms (2)

Exercise leg

EXPERIMENTAL

High-intensity exercise training for one leg

Behavioral: High-intensity exercise training

Control leg

NO INTERVENTION

No exercise training for the controlateral leg

Interventions

High-intensity exercise training BEHAVIORAL

Eight sessions of high-intensity interval exercise using a single-leg cycle ergometer are conducted on separate days over a 2-week period.

Also known as: High-intensity interval training

Exercise leg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Known m.3243A\>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene
• Other known mtDNA point mutations

You may not qualify if:

• Use of antiarrhythmic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
• Diagnosed severe heart disease, dysregulated thyroid gland conditions, or other dysregulated endocrinopathies, or other conditions which, in the opinion of the investigators, have the potential to affect outcome measures.
• Pregnancy

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• University of Copenhagen: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, Denmark, 2100, Denmark

Location

Related Publications (17)

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  PMID: 2044434 BACKGROUND

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  PMID: 26718503 BACKGROUND

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  PMID: 30067154 BACKGROUND

• O'Rahilly S. "Treasure Your Exceptions"-Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease: The 2019 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021 Jan;70(1):29-38. doi: 10.2337/dbi19-0037.

  PMID: 33355307 BACKGROUND

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  PMID: 28406212 BACKGROUND

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• Frederiksen AL, Jeppesen TD, Vissing J, Schwartz M, Kyvik KO, Schmitz O, Poulsen PL, Andersen PH. High prevalence of impaired glucose homeostasis and myopathy in asymptomatic and oligosymptomatic 3243A>G mitochondrial DNA mutation-positive subjects. J Clin Endocrinol Metab. 2009 Aug;94(8):2872-9. doi: 10.1210/jc.2009-0235. Epub 2009 May 26.

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• Lindroos MM, Majamaa K, Tura A, Mari A, Kalliokoski KK, Taittonen MT, Iozzo P, Nuutila P. m.3243A>G mutation in mitochondrial DNA leads to decreased insulin sensitivity in skeletal muscle and to progressive beta-cell dysfunction. Diabetes. 2009 Mar;58(3):543-9. doi: 10.2337/db08-0981. Epub 2008 Dec 10.

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• Deshmukh AS, Steenberg DE, Hostrup M, Birk JB, Larsen JK, Santos A, Kjobsted R, Hingst JR, Scheele CC, Murgia M, Kiens B, Richter EA, Mann M, Wojtaszewski JFP. Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training. Nat Commun. 2021 Jan 12;12(1):304. doi: 10.1038/s41467-020-20556-8.

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  PMID: 20028948 BACKGROUND

MeSH Terms

Conditions

Mitochondrial Myopathies; Mitochondrial Diseases; Insulin Resistance

Interventions

High-Intensity Interval Training

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperinsulinism; Glucose Metabolism Disorders

Intervention Hierarchy (Ancestors)

Physical Conditioning, Human; Exercise; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Matteo Fiorenza, Ph.D.

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

• John Vissing, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: In a within-subject parallel-group longitudinal design, participants sustain an exercise training intervention with one leg, while the contralateral leg serves as an inactive control.

Study Record Dates

• First Submitted: September 29, 2023
• First Posted: October 12, 2023
• Study Start: September 22, 2024
• Primary Completion: February 28, 2025
• Study Completion: February 28, 2025
• Last Updated: June 22, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)