Exercise-mediated Rescue of Mitochondrial Dysfunctions Driving Insulin Resistance

NCT ID: NCT06080594

Last Updated: 2025-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 11 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-22
• Study Completion Date: 2025-02-28

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

Detailed Description

Background: Peripheral insulin resistance is a major risk factor for metabolic diseases such as type 2 diabetes. Skeletal muscle accounts for the majority of insulin-stimulated glucose disposal, hence restoring insulin action in skeletal muscle is key in the prevention of type 2 diabetes. Mitochondrial dysfunction is implicated in the etiology of muscle insulin resistance. Also, as mitochondrial function is determined by its proteome quantity and quality, alterations in the muscle mitochondrial proteome may play a critical role in the pathophysiology of insulin resistance. However, insulin resistance is multifactorial in nature and whether mitochondrial derangements are a cause or a consequence of impaired insulin action is unclear. In recent years, the study of humans with genetic mutations has shown enormous potential to establish the mechanistic link between two physiological variables; indeed, if the mutation has a functional impact on one of those variables, then the direction of causality can be readily ascribed. Mitochondrial myopathies are genetic disorders of the mitochondrial respiratory chain affecting predominantly skeletal muscle. Mitochondrial myopathies are caused by pathogenic mutations in either nuclear or mitochondrial DNA (mtDNA), which ultimately lead to mitochondrial dysfunction. Although the prevalence of mtDNA mutations is just 1 in 5,000, the study of patients with mtDNA defects has the potential to provide unique information on the pathogenic role of mitochondrial derangements that is disproportionate to the rarity of affected individuals. The m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial leucyl-tRNA 1 gene is the most common mutation leading to mitochondrial myopathy in humans. The m.3243A>G mutation is associated with impaired glucose tolerance and insulin resistance in skeletal muscle. Most importantly, insulin resistance precedes impairments of β-cell function in carriers of the m.3243A>G mutation, making these patients an ideal human model to study the causative nexus between muscle mitochondrial dysfunction and insulin resistance. Exercise training is a potent stimulus to enhance muscle insulin action, improve mitochondrial function, and promote mitochondrial proteome remodeling. Accordingly, rescue of mitochondrial dysfunction has been proposed to play a role in the insulin-sensitizing effect of exercise. Yet, numerous mechanisms may contribute to the pathophysiology of insulin resistance and the beneficial effects of exercise may be linked to amelioration of multiple factors, thus challenging the interpretation of the functional significance of improved muscle mitochondrial function per se. Nevertheless, since mitochondrial dysfunction is likely the primary cause of muscle insulin resistance in carriers of the m.3243A>G mutation, prospective studies including an in-depth analysis of the mitochondrial adaptations elicited by exercise training in this cohort of patients may offer a unique opportunity to identify those mitochondrial derangements that, once rescued, drive enhancements in insulin sensitivity.

Objective: To study the effects of exercise training on muscle insulin sensitivity, muscle mitochondrial function, and the muscle mitochondrial proteome in individuals harboring pathogenic mitochondrial DNA (mtDNA) mutations associated with an insulin-resistant phenotype.

Study design: Within-subject parallel-group longitudinal study in individuals with pathogenic mtDNA mutations undergoing an exercise training intervention with one leg (contralateral leg as inactive control).

Endpoint: Differences between the trained and the untrained leg.

Conditions

Mitochondrial Myopathies; Mitochondrial Diseases; Mitochondrial Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Exercise leg

High-intensity exercise training for one leg

Group Type: EXPERIMENTAL

High-intensity exercise training

Intervention Type: BEHAVIORAL

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

Control leg

No exercise training for the controlateral leg

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

High-intensity exercise training

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

Intervention Type: BEHAVIORAL

Other Intervention Names

High-intensity interval training

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Copenhagen

OTHER

Sponsor Role: collaborator

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Matteo Fiorenza

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Matteo Fiorenza, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

John Vissing, MD

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Locations

Rigshospitalet

Copenhagen, Denmark, Denmark

Countries

Denmark

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Other Identifiers

EX-MITO-DYS-IR

Identifier Type: -

Identifier Source: org_study_id