Clinical trial NCT06080568: Human Mitochondrial Stress-driven Obesity Resistance
Official title: Energy Balance and Mitochondrial Function in Human Genetic Models of Mitochondrial Stress-mediated Obesity Resistance
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mitochondrial Diseases
Mitochondrial Myopathies
Mitochondrial Disorder
Keywords: Energy balance
Energy expenditure
Appetite
Energy intake
Mitochondrial dysfunction
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: University of Copenhagen
First posted: 2023-10-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals with mitochondrial myopathy due to pathogenic mtDNA mutations are identified and recruited from the Copenhagen Neuromuscular Center or the Department of Clinical Genetics (Rigshospitalet).

Control volunteers are recruited via recruitment announcements in Denmark.

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.

Eligibility 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

Exclusion criteria:

* Current and regular use of antidiabetic medications or other medications which, in the opinion of the investigators, have the potential to affect outcome measures.
* Diagnosed heart disease, symptomatic asthma, liver cirrhosis or -failure, chronic kidney 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
* Daily use of tobacco products
* Excessive alcohol consumption
* Pregnancy

Primary outcomes:
measure: Resting energy expenditure
timeFrame: Before (baseline) and 60-180 minutes after ingestion of a glucose solution
measure: Appetite
timeFrame: Before (baseline) and 60-180 minutes after ingestion of a glucose solution as well as immediately after an ad libitum meal test
measure: Energy intake
timeFrame: 180 minutes after ingestion of a glucose solution
Secondary outcomes:
measure: Plasma hormones and cytokines modulating appetite and energy expenditure
timeFrame: Before (baseline) and 0-180 minutes after ingestion of a glucose solution
measure: Plasma adipokines modulating appetite and energy expenditure
timeFrame: Baseline
measure: Muscle mitochondrial leak respiration
timeFrame: Baseline
measure: Muscle mitochondrial efficiency
timeFrame: Baseline
measure: Muscle mitochondrial membrane potential
timeFrame: Baseline
Other outcomes:
measure: Body composition
timeFrame: Baseline
measure: Physical activity level
timeFrame: Baseline
measure: Self-reported physical activity
timeFrame: Baseline
measure: Cardiorespiratory fitness
timeFrame: Baseline
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Matteo Fiorenza, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: John Vissing, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Copenhagen
name: Signe Torekov, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Guo Q, Xu Z, Zhou D, Fu T, Wang W, Sun W, Xiao L, Liu L, Ding C, Yin Y, Zhou Z, Sun Z, Zhu Y, Zhou W, Jia Y, Xue J, Chen Y, Chen XW, Piao HL, Lu B, Gan Z. Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4. Sci Adv. 2022 Jul 29;8(30):eabo0340. doi: 10.1126/sciadv.abo0340. Epub 2022 Jul 27.
citation: Yang M, Xu L, Xu C, Cui Y, Jiang S, Dong J, Liao L. The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients. Front Endocrinol (Lausanne). 2021 Nov 25;12:728043. doi: 10.3389/fendo.2021.728043. eCollection 2021.
citation: Sturm G, Karan KR, Monzel AS, Santhanam B, Taivassalo T, Bris C, Ware SA, Cross M, Towheed A, Higgins-Chen A, McManus MJ, Cardenas A, Lin J, Epel ES, Rahman S, Vissing J, Grassi B, Levine M, Horvath S, Haller RG, Lenaers G, Wallace DC, St-Onge MP, Tavazoie S, Procaccio V, Kaufman BA, Seifert EL, Hirano M, Picard M. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Commun Biol. 2023 Jan 12;6(1):22. doi: 10.1038/s42003-022-04303-x.
citation: 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.
citation: Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 Apr 12;544(7649):235-239. doi: 10.1038/nature22034.