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 d-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.
OHRI SEMINAR: Tuesday June 13, 2016, 3:30pm – 4:30pm
Title: “Therapeutic strategies and NAD+ metabolism in metabolic diseases, stem cell function and aging”
Increased NAD+ levels reduces stem cell aging, improves muscle function & increases lifespan in mice:
NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice
Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD+) and its impact on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD+ precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response (UPRmt) and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the Mdx mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs (NSCs) and melanocyte SCs (McSCs), and increased mouse lifespan. Strategies that conserve cellular NAD+ may reprogram dysfunctional SCs and improve lifespan in mammals.
An bright new student ready to lead the way in metabolism with a funding award from the Interdisciplinary School of Health Sciences.
Coming back to Canada from a scholarship in the US: Welcome back!
Here our work was highlighted in an article entitled: Boosting hepatic NAD+ prevents and reverses NAFLD in mice, published in Nature Reviews Gastroenterology & Hepatology.
“Few therapies are approved for the treatment of NAFLD. Now, researchers have shown that treatment with nicotinamide riboside, a precursor for NAD+ biosynthesis, can protect mice against the development of diet-induced NAFLD by increasing hepatic NAD+ levels.”