nicotinamide-beta-riboside and Mitochondrial-Myopathies

Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.. This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.. We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD. Increasing NAD

Topics: Adenine Nucleotide Translocator 1; Animals; Mice; Mitochondrial Myopathies; Muscle Weakness; NAD; Niacinamide; Physical Conditioning, Animal; Protein Isoforms; Pyridinium Compounds

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Topics: Acetylation; Acyl-CoA Dehydrogenase; Animals; Disease Models, Animal; Down-Regulation; Fatty Acids; Heart Failure, Diastolic; Humans; Ketone Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Myopathies; NAD; Niacinamide; Oxidation-Reduction; Oxygen Consumption; Pyridinium Compounds; Sirtuin 3

Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.

Topics: Adipose Tissue, Brown; Animals; Energy Metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Myopathies; Muscle, Skeletal; NAD; Niacinamide; Pyridinium Compounds; Sirtuin 1; Unfolded Protein Response; Vitamin B Complex

Mitochondrial diseases can arise from mutations either in mitochondrial DNA or in nuclear DNA encoding mitochondrially destined proteins. Currently, there is no cure for these diseases although treatments to ameliorate a subset of the symptoms are being developed. In this issue of EMBO Molecular Medicine, Khan et al (2014) use a mouse model to test the efficacy of a simple dietary supplement of nicotinamide riboside to treat and prevent mitochondrial myopathies.

Topics: Animals; Male; Mitochondria; Mitochondrial Myopathies; Niacinamide; Pyridinium Compounds; Vitamin B Complex