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Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle

ABSTRACT: NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE74570 | GEO | 2016/07/22

SECONDARY ACCESSION(S): PRJNA300850

REPOSITORIES: GEO

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Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle

Project description:NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. Messenger RNA was isolated from quadriceps muscle of mice from three different age groups and three different genotypes. Wildtype mice were aged 4, 7, and 24 months. Mice deficient for Nampt in skeletal muscle (mNKO) were aged 7 months. Mice overexpressing Nampt in skeletal muscle were aged 4 and 24 months.

2016-07-22 | E-GEOD-74570 | biostudies-arrayexpress

Collateral DNA damage and NAD+ dependence caused by reactive oxygen species signaling in inflammatory macrophages

Project description:Adoption of Warburg metabolism is critical for macrophage activation in response to lipopolysaccharide (LPS). Macrophages stimulated with LPS (without or with interferon-γ) increase expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ salvage, and loss of NAMPT activity alters their inflammatory potential. However, events leading to NAD+ salvage-dependence in these cells remain poorly defined. We show that NAD+ depletion and increased NAMPT expression occur rapidly after inflammatory activation and coincide with DNA damage caused by reactive oxygen species (ROS). ROS are produced by Complex III of the mitochondrial electron transport chain, and are required for macrophage activation. We show that DNA damage is associated with PARP activation, which results in NAD+ consumption and in this setting increased NAMPT expression allows the maintenance of NAD+ pools sufficient for GAPDH activity and Warburg metabolism. Our findings provide an integrated explanation for dependency on the NAD+ salvage pathway in inflammatory macrophages.

2019-03-06 | GSE123596 | GEO

Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway

Project description:Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in diverse cellular processes including metabolism, DNA repair, and aging. NAD metabolism is critical to maintain cellular homeostasis in response to environmental signals, however, how it is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer mammalian cells with the resistance to inhibitors of NAMPT, the rate limiting enzyme in the main vertebrate NAD salvage pathway. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a key precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. This bacteria-enabled bypass of the pharmacologically induced metabolic block in mammalian cells represents a novel paradigm in drug resistance. This host-microbe metabolic interaction also dramatically enhances the hepatic NAD-boosting efficiency of nicotinamide and nicotinamide riboside supplementation, demonstrating a crucial role of microbes, gut microbiota in particular, in systemic NAD metabolism.

2020-03-03 | GSE127750 | GEO

RNAi profiling of human MCF-7 cells depleted for NAMPT knockdown

Project description:NAMPT is an enzyme in the mammalian NAD+ salvage pathway. Expression microarray analysis was used to study the effect of NAMPT knockdown on gene expression in MCF-7 breast cancer cells. Experiment Overall Design: Stable knockdown of NAMPT was achieved using a retroviral shRNA construct. An shRNA directed against Luciferase was used to generate the Luc control cells. Three independent biological replicates with matching Luc controls were analyzed using Affymetrix U133 A2.0 microarrays.

2009-06-08 | E-GEOD-13449 | biostudies-arrayexpress

Expression analysis upon NAMPT knockdown in MCF-7 cells

2009-05-28 | GSE13449 | GEO

NAD+ metabolism governs proinflammatory senescence secretome

Project description:Cellular senescence is a stable cell growth arrest that is implicated in tissue aging and cancer. Senescent cells are characterized by an upregulation of proinflammatory and immunosuppressive cytokines and chemokines, which is termed as senescence-associated secretory phenotype (SASP). NAD+ metabolism plays a critical role in both tissue aging and cancer. However, the role of NAD+ metabolism in regulating the SASP is not well understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the strengths of proinflammatory SASP during senescence. In contrast to downregulation of NAMPT during replicative senescence, NAMPT is upregulated during oncogene-induced senescence. NAMPT selectively regulates proinflammatory, but not immunosuppressive, SASP. NAMPT is regulated by HMGA1 through a distal enhancer element during senescence. HMGA1/NAMPT/NAD+ signaling axis promotes proinflammatory SASP through enhancing glycolysis and mitochondria respiration. Mechanistically, HMGA1/NAMPT promotes proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFb activity. SASP regulation by NAD+ metabolism is independent of senescence-associated cell growth arrest. An increase in NAD+ levels is sufficient to convert SASP from low to high levels during replicative senescence. Together, we conclude that NAD+ metabolism governs the strengths of proinflammatory SASP. Given the tumor promoting effects of proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

2019-03-14 | GSE111841 | GEO

Nicotinamide riboside supplementation confers modest effects on skeletal muscle metabolism without mitochondrial and acetyl-proteome remodelingNicotinamide riboside supplementation confers modest effects on skeletal muscle metabolism without mitochondrial and acetyl-proteome remodeling

Project description:Nicotinamide riboside supplements (NRS) have been touted as a nutraceutical that promotes cardiometabolic and musculoskeletal health by enhancing nicotinamide adenine dinucleotide (NAD+) biosynthesis, mitochondrial function and/or the activities of NAD-dependent sirtuin deacetylase enzymes. This investigation examined the impact of NRS on whole body energy homeostasis, skeletal muscle mitochondrial function, and corresponding shifts in the acetyl-lysine proteome, in the context of diet-induced obesity using C57BL/6NJ mice. The study also included a genetically-modified mouse model that imposes greater demand on sirtuin flux and associated NAD+ consumption, specifically within muscle tissues. In general, whole body glucose control was modestly improved by NRS when administered at the midpoint of a chronic high fat diet, but not when given as a preventative therapy upon initiation of the diet. Contrary to anticipated outcomes, the study produced little evidence that NRS increases tissue NAD+ levels, augments mitochondrial function and/or mitigates diet-induced hyperacetylation of the skeletal muscle proteome.

2022-02-17 | PXD027904 | Pride

Cell Surface Expression with FK866

Project description:Maintenance of NAD+ levels by mitochondrial complex I, the NAD+ salvage pathway, and other routes is an important factor in of neurodegenerative disease and cancer. Both the production of NAD+ and the metabolic enzymes that require it as a redox cofactor or substrate differ widely in abundance across cell types and conditions. Disruption in the NAD+ supply thus exerts different effects depending on the cellular NAD+ requirements existing in the cell. Pharmacological depletion of NAD+ is actively being pursued in cancer and other diseases but these effects are not fully understood. Here, we combine quantitative proteomics and metabolomics to understand the consequences of disrupting cellular NAD+ levels and find that inhibiting the NAD+ salvage pathway depletes serine biosynthesis from glucose by impeding the NAD+-dependent protein 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, breast cancers that depend on PHGDH are exquisitely sensitive to blocking the NAD+ salvage pathway. PHGDH, and the rate-limiting enzyme of NAD+ salvage are also correlated in public tumor proteome and transcript datasets. These findings are immediately translatable to the pharmacological inhibition of NAMPT in PHGDH-dependent cancers.

2018-08-14 | PXD007791 | Pride

NAD Salvage Supports Serine Biosynthesis

2018-08-14 | PXD007790 | Pride

Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma (Mouse NAD targeted time-course)

Project description:NAMPT plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells was associated with down-regulation of genes relevant to QPRT-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also found that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but NMRK1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations was synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma. Mouse NAD targeted time-course is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS7253' rel='noopener noreferrer' target='_blank'>MTBLS7253</a>.Cell NAMPTi treatment is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7251' rel='noopener noreferrer' target='_blank'>MTBLS7251</a>.Mouse NAMPT targeted therapy is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS7252' rel='noopener noreferrer' target='_blank'>MTBLS7252</a>.

2023-10-10 | MTBLS7253 | MetaboLights

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