Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients
Condition: Mitochondrial Myopathies
MeSH terms: Muscular Diseases; Mitochondrial Myopathies
Study type: Interventional

Summary: 
      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.
    


Intervention name(s): Niacin
Intervention type(s): Dietary Supplement
Intervention description(s): 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.
Other intervention name(s): Nicotinic acid
Intervention MeSH terms: Niacin; Nicotinic Acids
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: All participants (healthy controls and mitochondrial myopathy patients) receive orally administered a slow-released form of niacin.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: vitamin B3; niacin; mitochondrial myopathy; mitochondria; muscle; muscle strength; NAD+ precursor; NAD+; NAD-booster