Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy methods
Aim. Evidence-backed execution summary for Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy methods from Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy.
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mouse
Subject model for the experiment.
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- confirm full cohort details in the source paper
NR-enriched diet protects the cardiac NAD + metabolome in HF
reagent used in the protocol.
- Use
- The impact of an NR-enriched diet on the cardiac NAD + metabolome is not known ( ). Mice fed with or without NR were sacrificed 3 days after the echocardiography at D50. Myocardial NAD was decreased in the SRF HKO mice at D50 as measured by the NAD cycling assay and the NR diet protected against this drop ( ). Myoca...
NR improves metabolism of citrate in HF
reagent used in the protocol.
- Use
- We noted that NR-treatment resulted in a net increase in acetylation of FOXO1 and p53 ( and ). Availability of cytosolic Ac-coA depends on mitochondrial citrate synthase (CS) production of citrate and conversion to Ac-coA via the cytosolic enzyme, ATP-citrate lyase (ACL). CS activity was reduced to 65% of control le...
Nmrk2 is induced by inhibition of alternative NAD + biosynthetic pathways in cultured cardiomyocytes
reagent used in the protocol.
- Use
- To assess the impact of NMRK2 on NAD + biosynthesis relative to the other pathways in cardiomyocytes, we used chemical inhibitors to target the alternative pathways in neonatal rat cardiomyocytes (NRC) grown in DMEM medium containing NAM as the vitamin B3. The glutamine analog azaserin (AZA) inhibits the glutamine-d...
What Is New?
reagent used in the protocol.
- Use
- An expression shift occurs in murine and human failing hearts in which the normally predominant NAMPT enzyme using nicotinamide as a precursor for NAD + synthesis is repressed whereas the NMRK2 enzyme using the nucleoside nicotinamide riboside (NR) is strongly upregulated.
NR preserves cardiac function in the TAC model
To determine whether NR treatment could be useful in other forms of HF, we assessed its efficiency in the TAC model of pressure overload cardiac hypertrophy. NR was administrated starting 2 days after the TAC or SHAM surgery. Kaplan-Meier survival curve analysis showed no significant difference, mainly because of a...
- Use
- To determine whether NR treatment could be useful in other forms of HF, we assessed its efficiency in the TAC model of pressure overload cardiac hypertrophy. NR was administrated starting 2 days after the TAC or SHAM surgery. Kaplan-Meier survival curve analysis showed no significant difference, mainly because of a...
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NR preserves cardiac function in the SRF HKO heart
We hypothesized that NR supplementation of food might be beneficial for cardiac function in the context of DCM. We fed control and mutant SRF HKO mice a standard chow diet (CD) or NR- supplemented diet to reach a dose of 400 mg/Kg of body weight/day from day 5 to 50, a period in which untreated SRF HKO mice develop DCM and progress toward HF. - NR-diet induced a modest 5 to 7 % increase in body weight in control mice and allowed SRF HKO mice to regain weight after an initial loss while SRF HKO mice on regular diet had lost weight at the end of the protocol ( ). Cardiac parameters were analyzed by echocardiography between D45-47 ( - ). NR did not change heart rate and LV mass index but slightly increased the LV thickness-to-radius ratio (H/R) in control mice ( ). To assess a potential impact of NR treatment on vascular function, we compared vascular reactivity in isol...
NR-enriched diet protects the cardiac NAD + metabolome in HF
The impact of an NR-enriched diet on the cardiac NAD + metabolome is not known ( ). Mice fed with or without NR were sacrificed 3 days after the echocardiography at D50. Myocardial NAD was decreased in the SRF HKO mice at D50 as measured by the NAD cycling assay and the NR diet protected against this drop ( ). Myocardial NAD + and NADH varied in the same direction in all conditions leaving the NAD + /NADH ratio unchanged ( ). LCMS analysis allowed us to provide the levels of NAD + metabolites on a common scale with NAD +, ( - ). SRF HKO mice hearts did not have higher levels of ADPR or NAM (, ). Levels of NADP + and NMN showed a similar pattern as NAD + (, ).
Nmrk2 is induced by inhibition of alternative NAD + biosynthetic pathways in cultured cardiomyocytes
We tested whether NR could preserve NAD + levels in the presence of FK866. NR slightly increased the baseline level of intracellular NAD + in non-treated NRC while exogenous NAD + had no impact ( ). Both compounds increased the NAD + /NADH ratio ( - ). NR fully protected NAD + levels in NRC treated with FK866 while the protection by exogenous NAD + was partial ( ), though both treatments blocked Nmrk2 induction ( ). At least 100 µM of NR was required to rescue the NAD + loss induced by 10 µM FK866 ( ). To assess the functionality of NMRK2 in absence of a stress like the FK866, we infected NRC with a recombinant adenovirus expressing HA-tagged Nmrk2 cDNA ( ). Overexpression of NMRK2 did not modulate the NAD + levels in NRC. In presence of NR, Nmrk2 overexpression robustly increased the NAD + level by a factor of 6. NR alone slightly increased the NAD + level in control...
NR preserves cardiac function in the TAC model
To determine whether NR treatment could be useful in other forms of HF, we assessed its efficiency in the TAC model of pressure overload cardiac hypertrophy. NR was administrated starting 2 days after the TAC or SHAM surgery. Kaplan-Meier survival curve analysis showed no significant difference, mainly because of a similar early mortality between the two groups within one week after TAC ( ). NR treatment reduced the final drop in LVEF that occurred between the 4 rth and 6 th week after TAC ( and ). NR did not attenuate the dilatation of the LV chamber and had only a transient effect on the thinning of the IVS (, ). At sacrifice, the cardiac hypertrophy index was similar between the CD and NR groups ( ).
Measurement outputs
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To explore possible alterations of NAD + homeostasis in the failing heart, we quantified expression of NAD + biosynthetic enzymes in human failing heart and in the heart of a mo...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Transcriptomic data are available on NCBI Gene Expression Database. Accession number: GSE84142.
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Animals were randomly assigned into different treatment groups. To assess significance, we performed Student's t test for independent samples when the experimental design...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
The impact of an NR-enriched diet on the cardiac NAD + metabolome is not known ( ). Mice fed with or without NR were sacrificed 3 days after the echocardiography at D50. Myocard...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Analysis plan
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Acquisition
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inferred from protocolPreprocessing / cleaning
Animals were randomly assigned into different treatment groups.
from paperScoring or quantification
Quantify the primary readouts for this experiment: To explore possible alterations of NAD + homeostasis in the failing heart, we quantified expression of NAD + biosynthetic enzymes in human failing heart and in the heart of a mo...; Transcriptomic data are available on NCBI Gene Expression Database. Accession number: GSE84142.; Animals were randomly assigned into different treatment groups. To assess significance, we performed Student's t test for independent samples when the experimental design...; The impact of an NR-enriched diet on the cardiac NAD + metabolome is not known ( ). Mice fed with or without NR were sacrificed 3 days after the echocardiography at D50. Myocard....
from paperStatistical comparison
Animals were randomly assigned into different treatment groups. To assess significance, we performed Student's t test for independent samples when the experimental design...; SRF HKO mutant mice fed the standard diet displayed a severe decrease in LV ejection fraction (LVEF) and fractional shortening (FS) (, ). The NR diet clearly protected against...; NR increased the cardiac levels of nicotinic acid adenine dinucleotide (NAAD) a sensitive biomarker of increased NAD + metabolism as well as Methyl-NAM (MeNAM) (, - ). Me...; To determine whether NR treatment could be useful in other forms of HF, we assessed its efficiency in the TAC model of pressure overload cardiac hypertrophy. NR was administrate...
from paperReporting output
Report representative outputs alongside summary comparisons for To explore possible alterations of NAD + homeostasis in the failing heart, we quantified expression of NAD + biosynthetic enzymes in human failing heart and in the heart of a mo..., Transcriptomic data are available on NCBI Gene Expression Database. Accession number: GSE84142., Animals were randomly assigned into different treatment groups. To assess significance, we performed Student's t test for independent samples when the experimental design..., The impact of an NR-enriched diet on the cardiac NAD + metabolome is not known ( ). Mice fed with or without NR were sacrificed 3 days after the echocardiography at D50. Myocard....
inferred from protocolStructured statistical methods
Animals were randomly assigned into different treatment groups. To assess significance, we performed Student's t test for independent samples when the experimental design...; SRF HKO mutant mice fed the standard diet displayed a severe decrease in LV ejection fraction (LVEF) and fractional shortening (FS) (, ). The NR diet clearly protected against...; NR increased the cardiac levels of nicotinic acid adenine dinucleotide (NAAD) a sensitive biomarker of increased NAD + metabolism as well as Methyl-NAM (MeNAM) (, - ). Me...; To determine whether NR treatment could be useful in other forms of HF, we assessed its efficiency in the TAC model of pressure overload cardiac hypertrophy. NR was administrate...
source structuredSource and audit
What supports the facts on this page?
Evidence quotes (4)
We hypothesized that NR supplementation of food might be beneficial for cardiac function in the context of DCM. We fed control and mutant SRF HKO mice a standard chow diet (CD) or NR- supplemented diet to reach a dose of 400 mg/Kg of body weight/day from day 5 to 50, a period in which untreated SRF HKO mice develop DCM and progress toward HF. - NR-diet induced a modest 5 to 7 % increase in body weight in control mice and allowed SRF HKO mice to regain weight after an initial loss while SRF HKO mice on regular diet had lost weight at the end of the protocol ( ). Cardiac parameters were analyzed by echocardiography between D45-47 ( - ). NR did not change heart rate and LV mass index but slightly increased the LV thickness-to-radius ratio (H/R) in control mice ( ). To assess a potential impact of NR treatment on vascular function, we compared vascular reactivity in isolated mesenteric arteries from NR-fed and control mice. We found no difference between the two groups neither in responses to K + or agonist-induced contraction nor in the relaxation response to carbachol or a NO donor ( and ).
The impact of an NR-enriched diet on the cardiac NAD + metabolome is not known ( ). Mice fed with or without NR were sacrificed 3 days after the echocardiography at D50. Myocardial NAD was decreased in the SRF HKO mice at D50 as measured by the NAD cycling assay and the NR diet protected against this drop ( ). Myocardial NAD + and NADH varied in the same direction in all conditions leaving the NAD + /NADH ratio unchanged ( ). LCMS analysis allowed us to provide the levels of NAD + metabolites on a common scale with NAD +, ( - ). SRF HKO mice hearts did not have higher levels of ADPR or NAM (, ). Levels of NADP + and NMN showed a similar pattern as NAD + (, ).
We tested whether NR could preserve NAD + levels in the presence of FK866. NR slightly increased the baseline level of intracellular NAD + in non-treated NRC while exogenous NAD + had no impact ( ). Both compounds increased the NAD + /NADH ratio ( - ). NR fully protected NAD + levels in NRC treated with FK866 while the protection by exogenous NAD + was partial ( ), though both treatments blocked Nmrk2 induction ( ). At least 100 µM of NR was required to rescue the NAD + loss induced by 10 µM FK866 ( ). To assess the functionality of NMRK2 in absence of a stress like the FK866, we infected NRC with a recombinant adenovirus expressing HA-tagged Nmrk2 cDNA ( ). Overexpression of NMRK2 did not modulate the NAD + levels in NRC. In presence of NR, Nmrk2 overexpression robustly increased the NAD + level by a factor of 6. NR alone slightly increased the NAD + level in control NRC infected with Ad-GFP ( ). In isolated primary cultures of adult rat cardiomyocytes (ARC), NR increased intracellular NAD nearly 3 fold showing that the NMRK pathway is more active in ARC than in NRC ( ). FK866 reduced NAD levels by a factor 2 ( ) in ARC and increased Nmrk2 expression by a factor...
To determine whether NR treatment could be useful in other forms of HF, we assessed its efficiency in the TAC model of pressure overload cardiac hypertrophy. NR was administrated starting 2 days after the TAC or SHAM surgery. Kaplan-Meier survival curve analysis showed no significant difference, mainly because of a similar early mortality between the two groups within one week after TAC ( ). NR treatment reduced the final drop in LVEF that occurred between the 4 rth and 6 th week after TAC ( and ). NR did not attenuate the dilatation of the LV chamber and had only a transient effect on the thinning of the IVS (, ). At sacrifice, the cardiac hypertrophy index was similar between the CD and NR groups ( ).
Machine-readable layer
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