Mitochondrial Diseases, Mitochondrial Disorder, Mitochondrial Myopathies
Conditions
Keywords
Energy balance, Energy expenditure, Appetite, Energy intake, Mitochondrial dysfunction
Brief summary
The overarching aim of this observational study is to determine alterations in energy balance while exploring the underlying cellular mechanisms in human genetic models of mitochondrial stress. In a case-control design, individuals with pathogenic mitochondrial DNA mutations will be compared to healthy controls matched for sex, age, and physical activity level. Participants will attend a screening visit and an experimental trial including assessments of energy expenditure, appetite sensation, energy intake, and muscle and subcutaneous adipose tissue biopsy samples.
Detailed description
Background: Pre-clinical models of mitochondrial stress are resistant to diet-induced obesity. Likewise, humans with primary mitochondrial diseases present a high prevalence of underweight (42%) as compared to a very low prevalence of obesity (2%). In this direction, recent data show a lower BMI across 17 cohorts of patients with mitochondrial diseases compared to national averages, suggesting mitochondrial stress-induced increments in resting energy expenditure as the primary driver of the lean phenotype. 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. Taken together, studies integrating assessments of energy balance with mitochondrial phenotyping in patients with rare mitochondrial disorders hold the potential to uncover putative mechanisms conferring protection from obesity in humans. Objective: To determine alterations in energy expenditure/intake while exploring the underlying cellular mechanisms in individuals harboring mitochondrial DNA (mtDNA) mutations associated with mitochondrial stress. Study design: Case-control study in individuals with mtDNA mutations (n=15) and healthy controls (n=15) matched for sex, age, and physical activity level. Endpoint: Differences between individuals with mtDNA mutations and controls.
Interventions
None listed
Sponsors
University of Copenhagen
Rigshospitalet, Denmark
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Eligibility criteria for individuals with mitochondrial DNA mutations Inclusion criteria: \- 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 Eligibility criteria for controls
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resting energy expenditure | Before (baseline) and 60-180 minutes after ingestion of a glucose solution | Resting energy expenditure is measured in the fasting and fed state by indirect calorimetry |
| Energy intake | 180 minutes after ingestion of a glucose solution | Energy intake is measured by quantifying the amount of food ingested during an ad libitum meal test |
| Appetite | Before (baseline) and 60-180 minutes after ingestion of a glucose solution as well as immediately after an ad libitum meal test | Subjective appetite sensations are measured in the fasting and fed state by visual analogue scale (VAS) ratings |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Muscle mitochondrial leak respiration | Baseline | Mitochondrial O2 flux is measured by high-resolution respirometry in permeabilized muscle fibers |
| Plasma hormones and cytokines modulating appetite and energy expenditure | Before (baseline) and 0-180 minutes after ingestion of a glucose solution | Plasma levels of FGF21, GDF15, GLP-1, PYY, ghrelin, glucagon, and GIP are measured in the fasting and fed state |
| Plasma adipokines modulating appetite and energy expenditure | Baseline | Plasma levels of leptin and adiponectin are measured in the fasting state |
| Muscle mitochondrial efficiency | Baseline | Mitochondrial P/O ratio is measured by high-resolution respirometry in isolated mitochondria |
| Muscle mitochondrial membrane potential | Baseline | Mitochondrial membrane potential is measured by high-resolution fluorometry in isolated mitochondria |
Other
| Measure | Time frame | Description |
|---|---|---|
| Physical activity level | Baseline | Physical activity level is measured by wrist-worn accelerometers |
| Cardiorespiratory fitness | Baseline | Pulmonary maximal oxygen uptake (VO2max) is determined during an incremental exercise test to exhaustion |
| Body composition | Baseline | Fat free mass and fat mass are determined by dual-energy X-ray absorptiometry |
| Self-reported physical activity | Baseline | Self-reported physical activity is measured by the International Physical Activity Questionnaire - Short Form (IPAQ-SF) |
Countries
Denmark
Outcome results
None listed