Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients


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.

Full Title of Study: “The Effect of Niacin Supplementation on Systemic Nicotinamide Adenine Dinucleotide (NAD+) Metabolism, Physiology and Muscle Performance in Healthy Controls and Mitochondrial Myopathy Patients”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Basic Science
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 31, 2017


  • 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.

Arms, Groups and Cohorts

  • Experimental: Niacin in controls
    • The arm includes healthy controls supplemented with niacin.
  • Experimental: Niacin in mitochondrial myopathy patients
    • The arm includes mitochondrial myopathy patients supplemented with niacin.

Clinical Trial Outcome Measures

Primary Measures

  • NAD+ and related metabolite levels in blood and muscle
    • Time Frame: Baseline, 4 months and 10 months
    • 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

Secondary Measures

  • Number of diseased muscle fibers
    • Time Frame: Baseline, 4 months and 10 months
    • 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
  • Mitochondrial biogenesis
    • Time Frame: Baseline, 4 months and 10 months
    • Change in mitochondria immunohistochemical staining intensity
  • Muscle mitochondrial oxidative capacity
    • Time Frame: Baseline, 4 months and 10 months
    • Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
  • Muscle metabolomic profile
    • Time Frame: Baseline, 4 months and 10 months
    • Change in muscle metabolite concentrations measured with mass spectrometry
  • Core muscle strength
    • Time Frame: Baseline, 4 months and 10 months
    • Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)
  • Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)
    • Time Frame: Baseline, 4 months and 10 months
    • Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits
  • Muscle mitochondrial DNA deletions
    • Time Frame: Baseline, 4 months and 10 months
    • Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
  • Muscle transcriptomic profile
    • Time Frame: Baseline, 4 months and 10 months
    • Change in muscle gene expression determined using RNA sequencing approach

Participating in This Clinical Trial

Inclusion Criteria

1. Manifestation of pure mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA 2. Age and gender matched healthy controls for every patient 3. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study 4. Written, informed consent to participate in the study Exclusion Criteria:

1. Inability to follow study protocol 2. Pregnancy or breast-feeding at any time of the trial 3. Malignancy that requires continuous treatment 4. Unstable heart disease 5. Severe kidney disease requiring treatment 6. Severe encephalopathy 7. Regular usage of intoxicants

Gender Eligibility: All

Minimum Age: 17 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Helsinki
  • Collaborator
    • Helsinki University Central Hospital
  • Provider of Information About this Clinical Study
    • Principal Investigator: Anu Wartiovaara, Academy Professor, Professor of Clinical Molecular Medicine – University of Helsinki
  • Overall Official(s)
    • Anu Suomalainen Wartiovaara, MD,PhD, Principal Investigator, Research Programs Unit, University of Helsinki, Helsinki, Finland


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