Niacin Cures Systemic NAD Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy.

Mark S Schmidt, Anu Suomalainen, Kirsi H Pietiläinen, Vidya Velagapudi, Charles Brenner, Marja-Riitta Taskinen, Nina Lundbom, Päivi Piirilä, Kimmo Haimilahti, Eija Pirinen, Ulla Heinonen, Juho Kuula, Antti Hakkarainen, Alberto Pessia, Niina Urho, Virginia Brilhante, Nahid A Khan, Mari Auranen

Journal: Cell metabolism 2021;31(6):1078-1090.e5

PMID: 32386566

Free Full Text on Elsevier Science View on PubMed

Plain Language Summary

Nicotinamide adenine dinucleotide (NAD+) metabolite and its derivatives are fundamental orchestrators of daily homeostasis in our tissues. The relative amounts of NAD forms (NAD+, NADH, NADP, and NADPH) and their cofactor functions to drive metabolism to either catabolic or anabolic direction, deciding whether nutrients are broken down to synthesize ATP (adenosine 5′-triphosphate), the cellular energy currency or used as building blocks for growth and repair. An increased NAD+ /NADH ratio is a signal for a low nutrient state activating cellular fasting responses. The main question of this study was whether NAD+ levels are depleted in mitochondrial dysfunction, as mitochondria are regulating NAD+ concentrations, and if so, whether NAD+ deficiency can be restored in the tissues of the patients. Results show that mitochondrial muscle disease causes NAD+ deficiency, a myopathy-induced vitamin B3 deficiency, a metabolic pellagra. Furthermore, NAD+ levels can be rescued by a potent NAD+ booster niacin, a vitamin B3 form. Authors conclude that their findings (1) underscore the potent role of micronutrient vitamin B3 as a metabolic modifier; (2) identify NAD+ deficiency as a contributor to mitochondrial myopathy progression; (3) point to usefulness of niacin therapy for progressive external ophthalmoplegia patients; (4) introduce blood NAD+ test as a tool to identify and follow-up NAD+ deficiency; (5) indicate that correction of metabolome and function can occur without correction of transcriptional stress responses, emphasizing importance of metabolomic analysis in follow-up of treatment efficacy.

Abstract

NAD is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD depletion occurs in patients with degenerative disorders and whether NAD repletion improves their symptoms has remained open. Here, we report systemic NAD deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.govNCT03973203) for patients and their matched controls for 10 or 4 months, respectively. Blood NAD increased in all subjects, up to 8-fold, and muscle NAD of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%. Our evidence indicates that blood analysis is useful in identifying NAD deficiency and points niacin to be an efficient NAD booster for treating mitochondrial myopathy.

Address: Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland. Electronic address: [email protected].; Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland.; Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.; Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland.; Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), Helsinki 00290, Finland.; Department of Radiology, Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo 12200, Finland.; Department of Radiology, Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.; Unit of Clinical Physiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.; Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Obesity Centre, Abdominal Centre, Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.; Research Program of Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; HUSlab, Helsinki University Hospital, Helsinki 00290, Finland; Neuroscience Center, HiLife, University of Helsinki, Helsinki 00290, Finland. Electronic address: [email protected].

DOI: 10.1016/j.cmet.2020.04.008