scholarly journals Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle

2020 ◽  
Author(s):  
David Frederick ◽  
Alan V. McDougal ◽  
Melisa Semenas ◽  
Johanna Vappiani ◽  
Andrea Nuzzo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nicotinamide Adenine Dinucleotide ◽  
Muscle Wasting ◽  
Therapeutic Benefit ◽  
Mdx Mice ◽  
Molecular Phenotype ◽  
Nicotinamide Riboside ◽  
Adp Ribosyl Cyclase ◽  
Molecular Phenotypes ◽  
Muscle Damage Markers

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to lessen the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit by providing a biosynthetic precursor, nicotinamide riboside, or specifically inhibiting the NAD-degrading activity of the ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy effectively lessened muscle damage markers or improved hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions Intramuscular NAD depletion occurs rapidly after eccentic injury, with broad pleitropic effects on the molecular phenotype of the tissue. Currently available means of protecting or replenishing the muscle NAD pool via orally administered small molecules are insufficient to functionally restore dystrophin-deficient muscle.

scholarly journals Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle

2020 ◽  
Author(s):  
David Frederick ◽  
Alan V. McDougal ◽  
Melisa Semenas ◽  
Johanna Vappiani ◽  
Andrea Nuzzo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nicotinamide Adenine Dinucleotide ◽  
Muscle Wasting ◽  
Therapeutic Benefit ◽  
Mdx Mice ◽  
Molecular Phenotype ◽  
Nicotinamide Riboside ◽  
Adp Ribosyl Cyclase ◽  
Molecular Phenotypes ◽  
Muscle Damage Markers

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to lessen the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit by providing a biosynthetic precursor, nicotinamide riboside, or specifically inhibiting the NAD-degrading activity of the ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy effectively lessened muscle damage markers or improved hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions Intramuscular NAD depletion occurs rapidly after eccentic injury, with broad pleitropic effects on the molecular phenotype of the tissue. Currently available means of protecting or replenishing the muscle NAD pool via orally administered small molecules are insufficient to functionally restore dystrophin-deficient muscle.

scholarly journals Complementary NAD+ Replacement Strategies Fail to Functionally Protect Dystrophin-Deficient Muscle

2020 ◽  
Author(s):  
David Frederick ◽  
Alan V. McDougal ◽  
Melisa Semenas ◽  
Johanna Vappiani ◽  
Andrea Nuzzo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Benefit ◽  
Pentose Phosphate ◽  
Mdx Mice ◽  
Molecular Phenotype ◽  
Nicotinamide Riboside ◽  
Adp Ribosyl Cyclase ◽  
Molecular Phenotypes ◽  
Bulk Tissue ◽  
Muscle Damage Markers

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most chronically depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit using two complementary small molecule strategies: provision of a biosynthetic precursor, nicotinamide riboside, or specific inhibition of the NAD-degrading ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, with a pronounced impact on intermediates of the pentose phosphate pathway, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy sustainably increased the bulk tissue NAD pool, lessened muscle damage markers, or improved maximal hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions In the absence of dystrophin, eccentric injury contributes to chronic intramuscular NAD depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside. However, neither small molecule strategy is sufficient to protect or restore muscle function, undermining the therapeutic approach.

scholarly journals Complementary NAD+ replacement strategies fail to functionally protect dystrophin-deficient muscle

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
David W. Frederick ◽  
Alan V. McDougal ◽  
Melisa Semenas ◽  
Johanna Vappiani ◽  
Andrea Nuzzo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Contractile Function ◽  
Therapeutic Benefit ◽  
Pentose Phosphate ◽  
Mdx Mice ◽  
Molecular Phenotype ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Adp Ribosyl Cyclase ◽  
Molecular Phenotypes

Abstract Background Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults to the muscle during eccentric contractions (ECCs). Methods Using a metabolomics-based approach, we observed distinct and transient molecular phenotypes in muscles of dystrophin-deficient MDX mice subjected to ECCs. Among the most chronically depleted metabolites was nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor suggested to protect muscle from structural and metabolic degeneration over time. We tested whether the MDX muscle NAD pool can be expanded for therapeutic benefit using two complementary small molecule strategies: provision of a biosynthetic precursor, nicotinamide riboside, or specific inhibition of the NAD-degrading ADP-ribosyl cyclase, CD38. Results Administering a novel, potent, and orally available CD38 antagonist to MDX mice successfully reverted a majority of the muscle metabolome toward the wildtype state, with a pronounced impact on intermediates of the pentose phosphate pathway, while supplementing nicotinamide riboside did not significantly affect the molecular phenotype of the muscle. However, neither strategy sustainably increased the bulk tissue NAD pool, lessened muscle damage markers, nor improved maximal hindlimb strength following repeated rounds of eccentric challenge and recovery. Conclusions In the absence of dystrophin, eccentric injury contributes to chronic intramuscular NAD depletion with broad pleiotropic effects on the molecular phenotype of the tissue. These molecular consequences can be more effectively overcome by inhibiting the enzymatic activity of CD38 than by supplementing nicotinamide riboside. However, we found no evidence that either small molecule strategy is sufficient to restore muscle contractile function or confer protection from eccentric injury, undermining the modulation of NAD metabolism as a therapeutic approach for DMD.

scholarly journals Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway

2020 ◽  
Vol 21 (13) ◽  
pp. 4655
Author(s):  
Duo Feng ◽  
DongZhu Xu ◽  
Nobuyuki Murakoshi ◽  
Kazuko Tajiri ◽  
Rujie Qin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Electrophysiological Study ◽  
Redox Homeostasis ◽  
Calcium Handling ◽  
Nicotinamide Adenine ◽  
Chow Diet ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Riboside ◽  
Normal Chow

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF.

scholarly journals Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

2020 ◽  
Vol 21 (3) ◽  
pp. 932 ◽  
Author(s):  
Piera Filomena Fiore ◽  
Anna Benedetti ◽  
Martina Sandonà ◽  
Luca Madaro ◽  
Marco De Bardi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Muscle Regeneration ◽  
Muscle Wasting ◽  
Expression Level ◽  
Acute Injury ◽  
Mdx Mice ◽  
Muscle Stem Cells ◽  
Advanced Stages ◽  
And Performance ◽  
Dystrophic Mice

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.

scholarly journals NAD precursors cycle between host tissues and the gut microbiome

2021 ◽  
Author(s):  
Karthikeyani Chellappa ◽  
Melanie R McReynolds ◽  
Wenyun Lu ◽  
Xianfeng Zeng ◽  
Mikhail Makarov ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Nicotinic Acid ◽  
Gut Microbiome ◽  
Nicotinamide Adenine Dinucleotide ◽  
Proximal Part ◽  
Main Route ◽  
Nicotinamide Riboside ◽  
Dietary Consumption ◽  
Nad Synthesis ◽  
Host Tissues

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in both mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome. We find that preferred dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports gut microbiome NAD synthesis. In addition, the microbiome converts nicotinamide, originating from the host circulation, into nicotinic acid. Host tissues uptake and utilize this microbiome-derived nicotinic acid for NAD synthesis, maintaining circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

scholarly journals Cholesterol absorption blocker ezetimibe prevents muscle wasting in severe dysferlin‐deficient and mdx mice

2021 ◽  
Author(s):  
Zoe White ◽  
Marine Theret ◽  
Nadia Milad ◽  
Lin Wei Tung ◽  
William Wei‐Han Chen ◽  
...  
Keyword(s):  
Muscle Wasting ◽  
Cholesterol Absorption ◽  
Mdx Mice

scholarly journals Learning causal biological networks with the principle of Mendelian randomization

2017 ◽  
Author(s):  
Md. Bahadur Badsha ◽  
Audrey Qiuyan Fu
Keyword(s):  
Biological Networks ◽  
Network Inference ◽  
Mendelian Randomization ◽  
Learning Algorithm ◽  
General Purpose ◽  
Molecular Phenotype ◽  
Phenotype Data ◽  
Causal Graphs ◽  
Molecular Phenotypes ◽  
Inference Methods

AbstractAlthough large amounts of genomic data are available, it remains a challenge to reliably infer causal (i.e., regulatory) relationships among molecular phenotypes (such as gene expression), especially when many phenotypes are involved. We extend the interpretation of the Principle of Mendelian randomization (PMR) and present MRPC, a novel machine learning algorithm that incorporates the PMR in classical algorithms for learning causal graphs in computer science. MRPC learns a causal biological network efficiently and robustly from integrating genotype and molecular phenotype data, in which directed edges indicate causal directions. We demonstrate through simulation that MRPC outperforms existing general-purpose network inference methods and other PMR-based methods. We apply MRPC to distinguish direct and indirect targets among multiple genes associated with expression quantitative trait loci.

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