title: NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.
abstract: Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD+) synthesis, consistent with a potential role for the essential cofactor NAD+in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+biosynthesis. Replenishing NAD+stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr-/-mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures.
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Dongryeol
authors: D
authors: Ryu
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Hongbo
authors: H
authors: Zhang
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.|Laboratory of Molecular Biology of Exercise, School of Applied Science, University of Campinas, CEP 13484-350 Limeira, São Paulo, Brazil.
authors: Eduardo R
authors: ER
authors: Ropelle
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Vincenzo
authors: V
authors: Sorrentino
authors: Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA.
authors: Davi A G
authors: DA
authors: Mázala
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Laurent
authors: L
authors: Mouchiroud
authors: Interdisciplinary School of Health Sciences, University of Ottawa Brain and Mind Research Institute and Centre for Neuromuscular Disease, Ottawa, Ontario K1H 8M5, Canada.
authors: Philip L
authors: PL
authors: Marshall
authors: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors: Matthew D
authors: MD
authors: Campbell
authors: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors: Amir Safi
authors: AS
authors: Ali
authors: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors: Gary M
authors: GM
authors: Knowels
authors: Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Université Claude Bernard Lyon 1, CNRS UMR 5534, 69622 Villeurbanne, France.
authors: Stéphanie
authors: S
authors: Bellemin
authors: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Shama R
authors: SR
authors: Iyer
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Xu
authors: X
authors: Wang
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Karim
authors: K
authors: Gariani
authors: Department of Pharmacology, Weill Cornell Medical School, New York, NY 10065, USA.
authors: Anthony A
authors: AA
authors: Sauve
authors: Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland.
authors: Carles
authors: C
authors: Cantó
authors: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors: Kevin E
authors: KE
authors: Conley
authors: Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Université Claude Bernard Lyon 1, CNRS UMR 5534, 69622 Villeurbanne, France.
authors: Ludivine
authors: L
authors: Walter
authors: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Richard M
authors: RM
authors: Lovering
authors: Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA.
authors: Eva R
authors: ER
authors: Chin
authors: Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors: Bernard J
authors: BJ
authors: Jasmin
authors: Department of Radiology, University of Washington, Seattle, WA 98195, USA.
authors: David J
authors: DJ
authors: Marcinek
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. admin.auwerx@epfl.ch kmenzies@uottawa.ca.|Interdisciplinary School of Health Sciences, University of Ottawa Brain and Mind Research Institute and Centre for Neuromuscular Disease, Ottawa, Ontario K1H 8M5, Canada.
authors: Keir J
authors: KJ
authors: Menzies
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. admin.auwerx@epfl.ch kmenzies@uottawa.ca.
authors: Johan
authors: J
authors: Auwerx
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D017173:Caenorhabditis elegans; D002460:Cell Line; D016207:Cytokines / Q000737:chemistry; D005355:Fibrosis / Q000473:pathology; D020869:Gene Expression Profiling; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009135:Muscular Diseases / Q000473:pathology; D009136:Muscular Dystrophies / Q000473:pathology*; D009243:NAD / Q000737:chemistry*; D054409:Nicotinamide Phosphoribosyltransferase / Q000737:chemistry; D009602:Nitrosamines / Q000737:chemistry; D000074747:Poly ADP Ribosylation; D012333:RNA, Messenger / Q000378:metabolism; D014439:Tyramine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D016207:Cytokines; D009602:Nitrosamines; D012333:RNA, Messenger; D009243:NAD; D000244:Adenosine Diphosphate; C036243:N-nitroso-N-methyltyramine; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D014439:Tyramine