Skeletal Muscle NAD Depletion Does Not Accelerate Muscle Aging
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ABSTRACT:
PROVIDER: PRJNA1141964 | ENA |
REPOSITORIES: ENA
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Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post-translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, to what extent normal NAD concentration can be decreased without deleterious repercussions is unclear. Here, we describe a mouse model where NAMPT-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance did not cause tissue degeneration or dysfunction, as reflected in its unchanged morphology, contractility, and exercise tolerance. The lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings demonstrate that NAD depletion does not drive the age-related decline in skeletal muscle function.
2025-04-23 | GSE273462 | GEO
Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, the extent to which cellular NAD concentration can be decreased without deleterious repercussions is unclear. We generated a mouse model where nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance was associated with preserved tissue integrity and functionality, as demonstrated by its unchanged morphology, contractility, and exercise tolerance. This lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings indicate that NAD depletion does not contribute to age related declines in skeletal muscle function.
2025-04-23 | PXD061221 | Pride
Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post-translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, the extent to which cellular NAD concentration can be decreased without deleterious repercussions is unclear. We generated a mouse model where nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance was associated with preserved tissue integrity and functionality, as demonstrated by its unchanged morphology, contractility, and exercise tolerance. This lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings indicate that NAD depletion does not contribute to age-related decline in skeletal muscle function.
2025-04-09 | GSE282353 | GEO
Project description:NAD Depletion in Skeletal Muscle does not Compromise Muscle Function or Accelerate Aging
| PRJNA1188178 | ENA
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
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.
2016-07-22 | GSE74570 | GEO
Project description:In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity, but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but metabolic effects of NR and PT treatment were modest. We conclude that chronic elevation of skeletal muscle NAD+ by intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimes.
2022-02-08 | GSE194193 | GEO
Project description:NAD+is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.
2019-08-29 | GSE133261 | GEO
Project description:Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinases and it regulates a variety of protein kinases involved in cell survival, motility and proliferation. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD), which plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in orthotopic xenograft murine models using patient-derived BALL cells. Although KPT-9274 affected both PAK4 signaling pathways and NAD+ dependent pathways, B-ALL cell growth inhibition mediated by KPT-9274 was largely abolished by nicotinic acid supplementation, indicating that the inhibitory effect of KPT- 9274 on B-ALL cell growth was mainly exerted by NAD+ depletion through blockade of NAMPT enzyme activity. Moreover, we found that B-ALL cells were especially vulnerable to NAD+ depletion, and the susceptibility to treatment with KPT-9274 was related to the reduced NAD+ reserve in B-ALL cells. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL.
2017-05-01 | GSE86871 | GEO
Project description:Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential.
2019-08-16 | GSE108968 | GEO