NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.
- Ryu D Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Zhang H Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Ropelle ER Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Sorrentino V Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Mázala DA Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA.
- Mouchiroud L Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Marshall PL Interdisciplinary School of Health Sciences, University of Ottawa Brain and Mind Research Institute and Centre for Neuromuscular Disease, Ottawa, Ontario K1H 8M5, Canada.
- Campbell MD Department of Radiology, University of Washington, Seattle, WA 98195, USA.
- Ali AS Department of Radiology, University of Washington, Seattle, WA 98195, USA.
- Knowels GM Department of Radiology, University of Washington, Seattle, WA 98195, USA.
- Bellemin S Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Université Claude Bernard Lyon 1, CNRS UMR 5534, 69622 Villeurbanne, France.
- Iyer SR Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Wang X Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Gariani K Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Sauve AA Department of Pharmacology, Weill Cornell Medical School, New York, NY 10065, USA.
- Cantó C Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland.
- Conley KE Department of Radiology, University of Washington, Seattle, WA 98195, USA.
- Walter L Centre de Génétique et de Physiologie Moléculaires et Cellulaires, Université Claude Bernard Lyon 1, CNRS UMR 5534, 69622 Villeurbanne, France.
- Lovering RM Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
- Chin ER Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA.
- Jasmin BJ Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
- Marcinek DJ Department of Radiology, University of Washington, Seattle, WA 98195, USA.
- Menzies KJ Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. admin.auwerx@epfl.ch kmenzies@uottawa.ca.
- Auwerx J Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. admin.auwerx@epfl.ch kmenzies@uottawa.ca.
- 2016-11-01
Published in:
- Science translational medicine. - 2016
Adenosine Diphosphate
Animals
Caenorhabditis elegans
Cell Line
Cytokines
Fibrosis
Gene Expression Profiling
Inflammation
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Skeletal
Muscular Diseases
Muscular Dystrophies
NAD
Nicotinamide Phosphoribosyltransferase
Nitrosamines
Poly ADP Ribosylation
RNA, Messenger
Tyramine
English
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1126/scitranslmed.aaf5504
- PMID 27798264
- Persistent URL
- https://sonar.ch/global/documents/97024
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