Ryu Dongryeol, Zhang Hongbo, Ropelle Eduardo R, Sorrentino Vincenzo, Mázala Davi A G, Mouchiroud Laurent, Marshall Philip L, Campbell Matthew D, Ali Amir Safi, Knowels Gary M, Bellemin Stéphanie, Iyer Shama R, Wang Xu, Gariani Karim, Sauve Anthony A, Cantó Carles, Conley Kevin E, Walter Ludivine, Lovering Richard M, Chin Eva R, Jasmin Bernard J, Marcinek David J, Menzies Keir J, Auwerx Johan
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.
Sci Transl Med. 2016 Oct 19;8(361):361ra139. doi: 10.1126/scitranslmed.aaf5504.
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.
神经肌肉疾病通常由遗传性突变引起，导致进行性骨骼肌无力和退化。在正常健康小鼠的不同群体中，我们观察到与线粒体生物发生、肌营养不良蛋白-肌聚糖复合物以及烟酰胺腺嘌呤二核苷酸（NAD）合成相关的mRNA转录本丰度之间存在相关性，这与必需辅因子NAD在保护肌肉免受代谢和结构退化方面的潜在作用一致。此外，杜兴氏肌营养不良症（DMD）和其他肌肉疾病患者的骨骼肌转录组富含各种聚[腺苷5'-二磷酸（ADP）-核糖]聚合酶（PARP）和烟酰胺N-甲基转移酶（NNMT），这些酶是NAD的主要消耗者，参与包括炎症在内的多效性事件。在DMD的mdx小鼠模型中，我们观察到肌肉NAD水平显著降低，PARP活性同时增加，以及NAD生物合成的限速酶烟酰胺磷酸核糖转移酶（NAMPT）的表达降低。通过饮食补充烟酰胺核糖来补充NAD储存可改善mdx和mdx/Utr小鼠的肌肉功能和心脏病理，并逆转DMD秀丽隐杆线虫模型中的病理。NAD补充对mdx小鼠的影响依赖于线粒体功能和结构蛋白表达（α-肌营养不良素结合蛋白和δ-肌聚糖）的改善以及总体聚（ADP）-核糖基化、炎症和纤维化的减少。综合来看，这些研究表明，补充NAD可能对患有以PARP/NNMT基因表达特征为特征的肌营养不良症或其他神经肌肉退行性疾病的患者有益。
