An interventional study of Niacin in Mitochondrial Myopathies, sponsored by University of Helsinki. Completed. Open to participants aged 17 Years to 70 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-05-11.
Sponsored by University of Helsinki · Not applicable, Interventional, and Basic science
The most frequent form of adult-onset mitochondrial disorders is mitochondrial myopathy, often manifesting with progressive external ophthalmoplegia (PEO), progressive muscle weakness and exercise intolerance. Mitochondrial myopathy is often caused by single heteroplasmic mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions, the former being sporadic and latter caused by mutations in nuclear-encoded proteins of mtDNA maintenance. Currently, no curative treatment exists for this disease. The investigators have previously observed that supplementation with an NAD+ precursor vitamin B3, nicotinamide riboside, prevented and delayed disease symptoms by increasing mitochondrial biogenesis in a mouse model for mitochondrial myopathy. Vitamin B3 exists in several forms: nicotinic acid (niacin), nicotinamide, and nicotinamide riboside, and it has been demonstrated to give power to diseased mitochondria in animal studies by increasing intracellular levels of NAD+, the important cofactor required for the cellular energy metabolism.
In this study, the form of vitamin B3, niacin, was used to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy. Of the vitamin B3 forms, niacin, is employed, because it has been used in large doses to treat hypercholesterolemia patients, and has a proven safety record in humans. Phenotypically similar mitochondrial myopathy patients are studied, as the investigator's previous expertise indicates that similar presenting phenotypes predict uniform physiological and clinical responses to interventions, despite varying genetic backgrounds. Patients either with sporadic single mtDNA deletions or a mutation in a Twinkle gene causing multiple mtDNA deletions were recruited. In addition, for every patient, two gender- and age-matched healthy controls are recruited. Clinical examinations and collection of muscle biopsies are performed at the time points 0, 4 and 10 months (patients) or at 0 and 4 months (controls). Fasting blood samples are collected every second week until 4 months and thereafter every six weeks until the end of the study. The effects of niacin on disease markers, muscle mitochondrial biogenesis, muscle strength and the metabolism of the whole body are studied in patients and healthy controls.
The hypothesis is that an NAD+ precursor, niacin, will increase intracellular NAD+ levels, improve mitochondrial biogenesis and alleviate the symptoms of mitochondrial myopathy in humans.
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Exclusion Criteria:
The arm includes healthy controls supplemented with niacin.
Dietary Supplement: Niacin
The arm includes mitochondrial myopathy patients supplemented with niacin.
Dietary Supplement: Niacin
The dose for a slow-released form of niacin will be 750-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 3 months. The intervention time with the full niacin dose is 1 and 7 months for controls and patients, respectively, and subsequently total intervention time 4 and 10 months, respectively. At the end of the study, the daily dose will be decreased by 250 mg/month rate.
Also known as: Nicotinic acid
NAD+ and related metabolite levels in blood and muscle
Change in concentrations of NAD+ and related metabolites such as: nicotinamide adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide measured using high performance liquid chromatography-mass spectrometry
Time frame: Baseline, 4 months and 10 months
Number of diseased muscle fibers
Change in number of abnormal muscle fibers (frozen sections, in situ histochemical activity analysis of cytochrome c oxidase negative / succinate-dehydrogenase positive muscle fibers; and immunohistochemistry of complex I negative muscle fibers
Time frame: Baseline, 4 months and 10 months
Mitochondrial biogenesis
Change in mitochondria immunohistochemical staining intensity
Time frame: Baseline, 4 months and 10 months
Muscle mitochondrial oxidative capacity
Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
Time frame: Baseline, 4 months and 10 months
Muscle metabolomic profile
Change in muscle metabolite concentrations measured with mass spectrometry
Time frame: Baseline, 4 months and 10 months
Core muscle strength
Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)
Time frame: Baseline, 4 months and 10 months
Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)
Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits
Time frame: Baseline, 4 months and 10 months
Muscle mitochondrial DNA deletions
Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
Time frame: Baseline, 4 months and 10 months
Muscle transcriptomic profile
Change in muscle gene expression determined using RNA sequencing approach
Time frame: Baseline, 4 months and 10 months
Body weight and body composition
Change in body weight as well as fat mass and fat free mass measured with bioimpedance
Time frame: Baseline, 4 months and 10 months
Ectopic lipid accumulation, i.e. liver and muscle lipid content
Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy
Time frame: Baseline, 4 months and 10 months
Circulating lipid profiles
Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay
Time frame: Baseline, 4 months and 10 months
No study locations are listed for this record.
Plan to share: No
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