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Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle
Open accessAbstract
SUMMARY We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.
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TL;DR
Long-term pharmacological PARP inhibition with MRL-45696 improves mitochondrial function, endurance, and metabolic health in mice, and rescues mitochondrial defects in worm and human cell models. The effects require SIRT1 and are linked to increased mitochondrial respiratory complex abundance, mitochondrial translation, and UPRmt induction.
Key findings
- In HFD-fed male C57BL/6J mice, MRL-45696 (50 mg/kg/day, 18 wks) blunted diet-induced body weight gain and fat accumulation, increased energy expenditure without changing activity or food intake, reduced skeletal muscle total PARP activity by −50%, increased muscle NAD+, and activated SIRT1 (lower FOXO1 acetylation) but not SIRT3.
- In chow-fed mice, MRL-45696 increased running distance, VO2max, maximal respiration in permeabilized EDL fibers, citrate synthase activity, oleic acid oxidation by ~50%, oxidative fiber markers (MHCI increased, MHCIIb decreased), and insulin sensitivity; these effects were absent in muscle-specific SIRT1-deficient mice.
- MRL-45696 increased mitochondrial respiratory complex abundance without changing mtDNA abundance, enhanced mitochondrial but not cytosolic protein translation, caused mitonuclear protein imbalance, and increased UPRmt markers ClpP and Hsp60.
- In BXD mouse strains, muscle Parp-1 expression varied 1.3-fold and negatively correlated with night VO2, VO2max improvement after 10 days training, and Tnni1, while positively correlating with body weight, Tnnc2, and Tnni2; in C. elegans mev-1 mutants, MRL-45696 inhibited PARP and increased OCR, and in NDUFS1 mutant human fibroblasts (complex I activity reduced by 87%) and primary myotubes from obese humans, it increased NAD+, OCR, lipid oxidation, and citrate synthase activity.
Methods
- In vitro studies used C2C12 myotubes, MEFs, NDUFS1 mutant human fibroblasts, and primary myotubes from obese patients; PARP inhibitors compared included BSI-201, PJ-34, ABT-888, AZD-2281, and MRL-45696, with assays for NAD+, redox potential, mitochondrial membrane potential, OCR, translation, and mitochondrial complexes.
- In vivo studies used 10-week-old male C57BL/6J mice fed HFD or chow with MRL-45696 (50 mg/kg/day) for 18 wks, SIRT1skm−/− mice, BXD mouse genetic reference population correlations via GeneNetwork, and C. elegans mev-1 mutants; analyses included respirometry in permeabilized EDL fibers, hyperinsulinemic-euglycemic clamp, histology, blue native page, and statistics by t-test or ANOVA with p<0.05.
Limitations
- The paper states that further work must be done to ensure the safety and feasibility of PARP inhibitors for non-life-threatening diseases, and it notes prior concerns about chronic genomic instability and combined PARP-1/PARP-2 inhibition.
- Evident from the text: many molecular and cellular protocols are in Supplemental Procedures rather than the main text, several outcomes (e.g., running distance) lack exact numerical values, human evidence comes from cultured fibroblasts and myotubes rather than clinical trials, and mouse findings rely on male C57BL/6J and specific genetic models.
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44 Own result · 33 Not checked yet · 16 Own interpretation
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In the paper
“Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity.”
- Also stated in: § PARP inhibition enhances endurance and mitochondrial function · plain
“Despite similar body weight and composition (Figures S3A–S3C), MRL-45696-treated mice ran for a significantly longer distance (Figure 2A).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
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- Also stated in: § PARP inhibition enhances endurance and mitochondrial function · plain
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In the paper
“Maximal O2 consumption capacity (VO2max), which critically determines endurance performance, was significantly higher with MRL-45696 (Figure S3D).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In line with PARP inhibition, intracellular NAD+ content was higher in muscle from treated mice (Figure 1I).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis.”
- Also stated in: § Parp-1 expression negatively correlates with energy expenditure · plain
“Parp-1 expression in muscles of the BXDs strains was negatively correlated with night VO2, VO2max improvement after 10 days training and with expression of the troponin I type 1 slow-twitch muscle isoform (Tnni1) (Figure 4B).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
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- Rests on an assumption: Parp-1 expression levels in skeletal muscle serve as a proxy for PARP-1 activity.
- Also stated in: § Parp-1 expression negatively correlates with energy expenditure · plain
In the paper
“Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans.”
- Also stated in: § Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function · plain
“MRL-45696 effectively inhibited PARP activity (Figure 4C) and OCR in mev-1 mutants (Figure 4D), as previously noticed in wild-type worms using other Paribs (Mouchiroud et al., 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
What the sources say
- Not checked yetcites Mouchiroud et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: C. elegans mev-1 mutants are a valid model for genetic mitochondrial defects in humans.
- Also stated in: § Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function · plain
In the paper
“Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans.”
- Also stated in: § Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function · plain
“MRL-45696 efficiently prevented H2O2-induced PARP activation (Figure 4F) and increased NAD+ (Figure 4G) in NDUFS1 mutant fibroblasts.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
What the sources say
- Not checked yetcites Bugiani et al., 2004 source
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- Rests on an assumption: NDUFS1 mutant fibroblasts are a valid model for genetic mitochondrial defects in humans.
- Also stated in: § Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MRL-45696 reduced the redox potential in C2C12 myotubes at concentrations as low as 1–10nM (Figure S1A), and increased mitochondrial membrane potential (MMP) (Figure S1B) and O2 consumption rates (OCR) at 10nM (Figure S1C).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Characterization of Paribs in C2C12 myotubes
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In the paper
“Conversely, the unaltered mitochondrial NAD+ levels did not change SIRT3 activity, as manifested in the acetylation of Ndufa9 (Figure 1L).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity.”
- Also stated in: § MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt · plain
“MRL-45696 increased the abundance of mitochondrial complexes, but did not change their mobility (Figure 3A).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
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- Also stated in: § MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity.”
- Also stated in: § PARP inhibition enhances endurance and mitochondrial function · plain
“Maximal respiration in the coupled state, with electron input through either complex I alone - using malate, pyruvate and glutamate - or complex I+II - using, in addition, succinate - was markedly higher in muscles after MRL-45696 (Figure 2B).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § PARP inhibition enhances endurance and mitochondrial function · plain
In the paper
“Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans.”
- Also stated in: § Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function · plain
“MRL-45696 effectively abrogated PARP activation, enhanced NAD+ levels (Figures 4K and 4L) and stimulated OCR (Figure 4M) in primary myotubes from obese patients (Timmers et al., 2012).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
What the sources say
- Not checked yetcites Timmers et al., 2012 source
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- Rests on an assumption: Primary myotubes from obese patients are a valid model for skeletal muscle mitochondrial function in obese humans.
- Also stated in: § Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite similar body weight and composition (Figures S3A–S3C), MRL-45696-treated mice ran for a significantly longer distance (Figure 2A).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“MRL-45696 blunted HFD-induced body weight gain (Figure 1A) due to reduced fat accumulation (Figure 1B) and was associated with higher energy expenditure (Figure 1C), without affecting activity or food intake (Figures 1D and 1E).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
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In the paper
“We initially determined that dietary admixture achieved higher MRL-45696 levels in plasma and muscle than oral gavage (Figures S2A and S2B), hence choosing this route for further studies.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
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“Increased mitochondrial translation, without according changes in cytosolic translation rates, can lead to mitonuclear protein imbalance (Houtkooper et al., 2013), which was evidenced by altered protein ratios between MTCO1, which is encoded by mtDNA, and SDHA, encoded by nDNA, induced by MRL-45696 (Figures 3E and 3F).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
What the sources say
- Not checked yetcites Houtkooper et al., 2013 source
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In the paper
“Finally, Paribs increased oleic acid oxidation rates by ~50% (Figure 2D).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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In the paper
“While it is not clear how Paribs trigger mitonuclear imbalance and UPRmt in mammalian cells, results obtained in C2C12 cells suggest that SIRT1 is required for such an effect (Figure S4C), consistent with the mechanisms reported in worms (Mouchiroud et al., 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
What the sources say
- Not checked yetcites Mouchiroud et al., 2013 source
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In the paper
“As cardiovascular parameters, including ejection fraction, fractional shortening, ventricular mass and diameter (Figures S3E–S3I) were unchanged, the higher endurance was most likely due to improved muscle mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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“These results are consistent with the marked increase in citrate synthase (CS) activity after MRL-45595 (Figure 2C).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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“Furthermore, MHCI staining of gastrocnemius confirmed the higher type I fiber content after MRL-45696 (Figure 2H).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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In the paper
“Within the time-frame of this study, and in line with findings in Parp-1−/− mice (Bai et al., 2011) and in patients treated with Olaparib (Audeh et al., 2010; Bundred et al., 2013; Tutt et al., 2010), no toxicity or genomic instability was seen in MRL-45696-treated mice.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
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“Mitochondrial DNA abundance was, however, not changed (Figure 2E), suggesting that MRL-45696 does not influence muscle mitochondrial function by increasing mitochondrial number.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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“These changes in Parp-1 expression are not related to natural variations in fiber type composition, as Parp-1 expression is comparable in muscles having different fiber type content, such as gastrocnemius or soleus (data not shown).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
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In the paper
“Maximum electron transport system capacity was also higher after PARP inhibition, even after the addition of the complex I inhibitor rotenone (Figure 2B).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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“As MRL-45696 did not affect mRNA levels of mitochondrial complex subunits (Figure S4B), we speculated that the higher respiratory complex content could be due to enhanced mitochondrial protein translation.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
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“In line with this premise, ClpP and Hsp60 levels, which reflect the presence of UPRmt, were increased in MRL-45696 treated muscles (Figures 3E and 3F).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
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“Histological analysis further certified that Paribs enhanced the oxidative profile of skeletal muscle, as testified by more intense cytochrome c oxidase and succinate dehydrogenase staining in gastrocnemius (Figure 2F).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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In the paper
“Parp-1 expression varied 1.3-fold in skeletal muscle of the BXD strains, enabling the study of gene expression correlations (Figure 4A).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
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“In line with this hypothesis, MRL-45696 specifically increased mitochondrial, but not cytosolic (Figures 3B–3D), protein translation rates in MEFs.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
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In the paper
“The higher oxidative capacity after Paribs was accompanied by increased insulin sensitivity, as reflected by the higher glucose infusion rate during a hyperinsulinemic-euglycemic clamp (Figure S3J).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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In the paper
“Maximal respiration in the coupled state, with electron input through either complex I alone - using malate, pyruvate and glutamate - or complex I+II - using, in addition, succinate - was markedly higher in muscles after MRL-45696 (Figure 2B).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
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In the paper
“Importantly, PARP inhibition rescued mitochondrial activity in situations of genetically determined mitochondrial dysfunction.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
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In the paper
“indicating that variations in PARP-1 activity have an impact on metabolic homeostasis.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Parp-1 expression levels in skeletal muscle serve as a proxy for PARP-1 activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, PARP inhibition constitutes a plausible strategy to improve metabolic homeostasis.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
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In the paper
“Overall, our work validates in worm, mouse and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
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In the paper
“One strategy to increase NAD+ levels consists of the inhibition of alternative NAD+ consuming enzymes, such as poly(ADP-ribose) polymerase-1 (PARP-1) (Bai and Canto, 2012), which is involved in DNA damage detection and repair.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Bai and Canto, 2012 source
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In the paper
“Several studies have shown that NAD+ levels can be rate-limiting for the deacetylase activity of SIRT1, the best-characterized sirtuin (Canto and Auwerx, 2012).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Canto and Auwerx, 2012
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In the paper
“Consistent with this, PARP-1 activity was found to enhance adipogenesis (Erener et al., 2012).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
What the sources say
- Not checked yetcites Erener et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“To elucidate whether Paribs could recover mitochondrial function in models with genetically determined mitochondrial defects, we first used the C. elegans mev-1 strain, which contains a missense mutation in cyt-1, the worm homolog of mammalian succinate dehydrogenase cytochrome b, a component of complex II (Senoo-Matsuda et al., 2001).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Senoo-Matsuda et al., 2001 source
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In the paper
“In sum, this work provides evidence that drugs used at present in the cancer field could be retooled to treat metabolic dysfunction linked to impaired mitochondrial activity, even in a long-term fashion.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
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In the paper
“Hence, the interrelation between PARP activity and mitochondrial function is well conserved across the evolutionary spectrum from worms to mice and humans.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
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In the paper
“This robust genetic correlation suggests a physiological influence of PARP-1 activity on oxidative metabolism.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Parp-1 expression levels in skeletal muscle serve as a proxy for PARP-1 activity.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, increased respiratory chain complex content, rather than changes in complex composition or stoichiometry, accounts for the enhanced mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
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In the paper
“To test whether these observations could also apply in human models, we used skin fibroblasts from a patient with a mutation in the nuclear NDUFS1 gene, which reduced complex I activity by 87% (Bugiani et al., 2004).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Bugiani et al., 2004 source
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In the paper
“Increased mitochondrial translation, without according changes in cytosolic translation rates, can lead to mitonuclear protein imbalance (Houtkooper et al., 2013), which was evidenced by altered protein ratios between MTCO1, which is encoded by mtDNA, and SDHA, encoded by nDNA, induced by MRL-45696 (Figures 3E and 3F).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
What the sources say
- Not checked yetcites Houtkooper et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Oppositely, PARP activity was decreased in muscle upon fasting (Bai et al., 2011), when lipid oxidation is favored.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
What the sources say
- Not checked yetcites Bai et al., 2011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As cardiovascular parameters, including ejection fraction, fractional shortening, ventricular mass and diameter (Figures S3E–S3I) were unchanged, the higher endurance was most likely due to improved muscle mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Such a mitonuclear protein imbalance could trigger UPRmt to restore optimal mitochondrial function (Houtkooper et al., 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
What the sources say
- Not checked yetcites Houtkooper et al., 2013 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Hence, the inhibition of PARP actions on translational processes could be a complementary mechanism to explain the induction of UPRmt.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Notably, Paribs are in general well tolerated by patients with few reported side effects (Audeh et al., 2010; Bundred et al., 2013; Tutt et al., 2010).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Collectively, this indicates that physiological changes in PARP-1 activity might help balancing whole-body energy metabolism”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Finally, we evaluated whether Paribs could improve acquired defects in mitochondrial function, such as the decreased mitochondrial activity observed in skeletal muscle cells of obese humans (Patti and Corvera, 2010).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Patti and Corvera, 2010 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Therefore, SIRT1 seems key to the actions of Paribs on muscle metabolism.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Mitochondrial DNA abundance was, however, not changed (Figure 2E), suggesting that MRL-45696 does not influence muscle mitochondrial function by increasing mitochondrial number.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data therefore illustrate that Paribs enhance mitochondrial function in both acquired and genetically determined mitochondrial alterations.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, our results open the path of using Paribs to improve invalidating diseases caused by impaired mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 32
- Probably not a substantial claim. 7
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MRL-45696 blunted HFD-induced body weight gain (Figure 1A) due to reduced fat accumulation (Figure 1B) and was associated with higher energy expenditure (Figure 1C), without affecting activity or food intake (Figures 1D and 1E).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Reductions in PARP activity translated also into SIRT1 activation, as reflected by lower FOXO1 acetylation, despite slightly lowered SIRT1 levels (Figure 1K).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“MRL-45696, a dual PARP-1 and PARP-2 inhibitor derived from niraparib (Chinnaiyan et al., 2012; Jones et al., 2009) most efficiently rescued the H2O2-induced NAD+ decline, with a low nanomolar IC50 (Supplemental Table 1).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Characterization of Paribs in C2C12 myotubes
What the sources say
- Not checked yetcites Chinnaiyan et al., 2012
- Not checked yetcites Jones et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“MRL-45696 reduced the redox potential in C2C12 myotubes at concentrations as low as 1–10nM (Figure S1A), and increased mitochondrial membrane potential (MMP) (Figure S1B) and O2 consumption rates (OCR) at 10nM (Figure S1C).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Characterization of Paribs in C2C12 myotubes
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, MRL-45696 or AZD-2281 were not toxic at these concentrations, as ATP content was unaffected (Figures S1D and S1H).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Characterization of Paribs in C2C12 myotubes
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Although PARP-1 has been shown to impact genome stability and cell viability, no evidence for toxicity on genomic DNA or cellular damage was found, as liver 8-oxo-dG and muscle lipid peroxidation levels were similar between the groups (Figures 1F and 1G).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In agreement, nanomolar concentrations of AZD-2281 decreased redox potential, while increasing MMP and OCR (Figures S1E–S1G).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Characterization of Paribs in C2C12 myotubes
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The higher NAD+ levels were restricted to the nuclear and/or cytosolic compartments, since mitochondrial NAD+ content was similar between both groups (Figure 1J).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“MRL-45696 reduced total PARP activity in skeletal muscle (−50%; Figure 1H) and in others tissues tested, including brain and liver (Figure S2C).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MRL-45696 efficiently prevented H2O2-induced PARP activation (Figure 4F) and increased NAD+ (Figure 4G) in NDUFS1 mutant fibroblasts.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“MRL-45696 effectively inhibited PARP activity (Figure 4C) and OCR in mev-1 mutants (Figure 4D), as previously noticed in wild-type worms using other Paribs (Mouchiroud et al., 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Mouchiroud et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Of note, the expression of Sirt1, Tfam and c-myc was also increased in Parib treated muscles (Figure S3K), which indicates that a recently identified SIRT1-dependent pathway (Gomes et al., 2013) by which NAD+ controls metabolic health might also be at play.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
What the sources say
- Not checked yetcites Gomes et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, MRL-45696 granted a higher ability to oxidize lipids (Figure 4N), probably by enhancing mitochondrial function, as suggested by the higher CS activity (Figure 4O).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Primary myotubes from obese patients are a valid model for skeletal muscle mitochondrial function in obese humans.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In line with observations in mouse tissues, MRL-45696 also increased OCR (Figures 4H–4J), lipid oxidation and CS activity in these cells, testifying for enhanced mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MRL-45696 increased the abundance of mitochondrial complexes, but did not change their mobility (Figure 3A).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“MRL-45696 effectively abrogated PARP activation, enhanced NAD+ levels (Figures 4K and 4L) and stimulated OCR (Figure 4M) in primary myotubes from obese patients (Timmers et al., 2012).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Timmers et al., 2012
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Primary myotubes from obese patients are a valid model for skeletal muscle mitochondrial function in obese humans.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, an increase in slow oxidative MHCI, a marker for type I fibers, was observed, whereas MHCIIb levels, a type II fiber marker, were decreased by MRL-45696 (Figure 2G).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, Paribs were unable to enhance endurance, respiratory capacity and CS activity in the SIRT1skm−/− mice (Figures 2A–2C).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, Parp-1 positively correlated with body weight, troponin C type 2 fast-twitch muscle isoform (Tnnc2) and troponin I type 2 fast-twitch muscle isoform (Tnni2) (Figure 4B).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In line with previous reports (Menzies et al., 2013; Philp et al., 2011), endurance or VO2max was not impaired in SIRT1skm−/− mice (data not shown).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
What the sources say
- Not checked yetcites Menzies et al., 2013
- Not checked yetcites Philp et al., 2011
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The increased respiration also translated into effective prevention against age-related physiological decline, as old mev-1 mutants maintained youthful motility (Figure 4E).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Parp-1 expression in muscles of the BXDs strains was negatively correlated with night VO2, VO2max improvement after 10 days training and with expression of the troponin I type 1 slow-twitch muscle isoform (Tnni1) (Figure 4B).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, marked metabolic effects were observed, such as improved mitochondrial function and protection against diet-induced obesity.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > Abstract
What the sources say
- Not checked yetcites Bai et al., 2011 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“As a consequence, mitochondrial oxidative capacity is enhanced in muscle of Parp-1−/− mice, protecting them against high-fat diet (HFD)-induced insulin resistance.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Bai et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Genetic ablation of Parp-1 increases NAD+ availability and SIRT1 activity in tissues, such as skeletal muscle and brown adipose tissue (Bai et al., 2011).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Bai et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, our work sets the stage for the possible clinical use of Paribs in situations of defective mitochondrial function.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“The sirtuin enzymes have emerged as critical regulators of mitochondrial and oxidative metabolism (Chalkiadaki and Guarente, 2012).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Chalkiadaki and Guarente, 2012
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Reductions in mitochondrial number and activity are a hallmark of several inherited mitochondrial diseases, as well as a number of age-related neurodegenerative and metabolic disorders (Andreux et al., 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Andreux et al., 2013 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PARP inhibitors (Paribs) already exist and are clinically tested in the cancer field (Curtin and Szabo, 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > INTRODUCTION
What the sources say
- Not checked yetcites Curtin and Szabo, 2013 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Altogether, these results illustrate the robust effects of MRL-45696 on mitochondrial translation, which culminate in the induction of UPRmt.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The ability of complex II to catalyse electron transport from succinate to ubiquinone is compromised in mev-1 mutants, leading to increased superoxide levels and premature aging.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Senoo-Matsuda et al., 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Paribs increase mitochondrial respiratory capacity in worms by triggering the mitochondrial unfolded protein response (UPRmt-) in a SIRT1-dependent manner (Mouchiroud et al., 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
What the sources say
- Not checked yetcites Mouchiroud et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, previous results indicated that PARP activity is increased upon HFD (Bai et al., 2011), likely favouring fat storage over burning (Erener et al., 2012).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Parp-1 expression negatively correlates with energy expenditure
What the sources say
- Not checked yetcites Bai et al., 2011 source
- Not checked yetcites Erener et al., 2012
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The success of Paribs is thought to rely on the high dependency of these cancer cells on PARP enzymes for DNA repair (Curtin and Szabo, 2013), but could also involve their capacity to reprogram cells towards oxidative metabolism (Bai et al., 2011).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In addition, PARPs have been reported to silence translation during stress by binding and/or PARylating RNA-binding proteins that control the polyadenylation of mRNAs and protein translation rates (for review, see (Luo and Kraus, 2012)).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > MRL-45696 enhances mitochondrial protein translation and triggers the UPRmt
What the sources say
- Not checked yetcites Luo and Kraus, 2012
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Paribs are currently being tested for oncology indications, with positive outcomes in tumors with dysfunctional homologous DNA recombination repair (Curtin and Szabo, 2013).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
What the sources say
- Not checked yetcites Curtin and Szabo, 2013 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Parp-1 expression levels in skeletal muscle serve as a proxy for PARP-1 activity.
“Parp-1 expression varied 1.3-fold in skeletal muscle of the BXD strains, enabling the study of gene expression correlations (Figure 4A).”
“This robust genetic correlation suggests a physiological influence of PARP-1 activity on oxidative metabolism.”
The paper relies on this without support.
Primary myotubes from obese patients are a valid model for skeletal muscle mitochondrial function in obese humans.
“MRL-45696 effectively abrogated PARP activation, enhanced NAD+ levels (Figures 4K and 4L) and stimulated OCR (Figure 4M) in primary myotubes from obese patients (Timmers et al., 2012).”
The paper relies on this without support.
NDUFS1 mutant fibroblasts are a valid model for genetic mitochondrial defects in humans.
“To test whether these observations could also apply in human models, we used skin fibroblasts from a patient with a mutation in the nuclear NDUFS1 gene, which reduced complex I activity by 87% (Bugiani et al., 2004).”
The paper relies on this without support.
C. elegans mev-1 mutants are a valid model for genetic mitochondrial defects in humans.
“To elucidate whether Paribs could recover mitochondrial function in models with genetically determined mitochondrial defects, we first used the C. elegans mev-1 strain, which contains a missense mutation in cyt-1, the worm homolog of mammalian succinate dehydrogenase cytochrome b, a component of complex II (Senoo-Matsuda et al., 2001).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Alternatively, pharmacological inhibition of the NAD+ consuming enzyme poly (ADP-ribose) polymerase in mice activates SIRT1 and increases mitochondrial respiratory capacity leading to augmented fitness and protection from diet-induced obesity (268).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [268]
In the citing paper
“Moreover, poly (ADP-ribose) polymerase inhibition rescued mitochondrial respiration defects and increased FAO in myotubes from obese patients by augmenting mitochondrial function (268).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [268]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
“These results are consistent with the marked increase in citrate synthase (CS) activity after MRL-45595 (Figure 2C).”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > PARP inhibition enhances endurance and mitochondrial function
“Despite similar body weight and composition (Figures S3A–S3C), MRL-45696-treated mice ran for a significantly longer distance (Figure 2A).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Chronic PARP inhibition enhances energy expenditure and SIRT1 activity
“We next fed HFD admixed with MRL-45696 (50 mg/kg/day) to 10-wk old male C57BL/6J mice.”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > EXPERIMENTAL PROCEDURES > In vivo and ex vivo studies
“For the long-term animal studies, 10-week-old male C57BL/6J mice (Charles River) or SIRT1skm−/− mice were fed pellets containing either vehicle and/or PARP inhibitor (50 mg/g/kg) for 18wks.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
“MRL-45696 effectively inhibited PARP activity (Figure 4C) and OCR in mev-1 mutants (Figure 4D)”
§ Pharmacological Inhibition of Poly(ADP-Ribose) Polymerases Improves Fitness and Mitochondrial Function in Skeletal Muscle > RESULTS AND DISCUSSION > Paribs improve oxidative capacity in worm and human models of reduced mitochondrial function
“The increased respiration also translated into effective prevention against age-related physiological decline, as old mev-1 mutants maintained youthful motility (Figure 4E).”
Citations
Cites
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.11.013 · Cited by 4,057
Self-citationAMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., & Auwerx, J. (2009) · Nature · doi:10.1038/nature07813 · Cited by 3,300
Self-citationAudeh, M. W., Carmichael, J., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, K. M., Scott, C., Weitzel, J. N., Oaknin, A., Loman, N., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60893-8 · Cited by 2,279 · cited 1×
“Notably, Paribs are in general well tolerated by patients, with few reported side effects (Audeh et al., 2010; Bundred et al., 2013; Tutt et al., 2010).”
BackgroundSirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · cited 1×
“The sirtuin enzymes have emerged as critical regulators of mitochondrial and oxidative metabolism (Houtkooper et al., 2012).”
BackgroundSelf-citationSUnSET, a nonradioactive method to monitor protein synthesis
Schmidt, E. K., Clavarino, G., Ceppi, M., & Pierre, P. (2009) · Nature Methods · doi:10.1038/nmeth.1314 · Cited by 1,706
SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation
Hirschey, M. D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D. B., Grueter, C. A., Harris, C., Biddinger, S., Ilkayeva, O. R., et al. (2010) · Nature · doi:10.1038/nature08778 · Cited by 1,687
Tutt, A., Robson, M., Garber, J. E., Domchek, S. M., Audeh, M. W., Weitzel, J. N., Friedlander, M., Arun, B., Loman, N., Schmutzler, R. K., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60892-6 · Cited by 1,655 · cited 2×
“Within the time frameof this study, and in linewith findings inParp-1 / mice (Bai et al., 2011) and in patients treatedwithOlaparib (Audehet al., 2010; Bundred et al., 2013; Tutt et al., 2010), no toxicity or genomic instability was seen in MRL-45696-treated mice.”
BackgroundResultGomes, A. P., Price, N. L., Ling, A. J. Y., Moslehi, J. J., Montgomery, M. K., Rajman, L., White, J. P., Teodoro, J. S., Wrann, C. D., Hubbard, B. P., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.037 · Cited by 1,482 · cited 2×
“Of note, the expression of Sirt1, Tfam, and c-mycwas also increased in Parib-treated muscles (Figure S3K), which indicates that a recently identified SIRT1-dependent pathway (Gomes et al., 2013) by which NAD+ controls metabolic health might also be at play.”
BackgroundMouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.016 · Cited by 1,210 · cited 5×
“MRL-45696 Enhances Mitochondrial Protein Translation and Triggers the UPR Paribs increase mitochondrial respiratory capacity in worms by triggering the mitochondrial unfolded protein response (UPR) in a SIRT1-dependent manner (Mouchiroud et al., 2013).”
BackgroundResultInfluentialSelf-citationOrganelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts
Frezza, C., Cipolat, S., & Scorrano, L. (2007) · Nature Protocols · doi:10.1038/nprot.2006.478 · Cited by 1,188
Cited by
Sorted by citations
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648
Self-citationNAD+ metabolism and its roles in cellular processes during ageing
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00313-x · Cited by 1,617
Gorman, G. S., Chinnery, P. F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R., Suomalainen, A., Thorburn, D. R., Zeviani, M., & Turnbull, D. M. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.80 · Cited by 1,650
Self-citationNAD + in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319
NAD + repletion improves mitochondrial and stem cell function and enhances life span in mice
Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., et al. (2016) · Science · doi:10.1126/science.aaf2693 · Cited by 1,255
Self-citation
Metadata
- Authors
- Pirinen, E., Cantó, C., Jo, Y. S., Morato, L., Zhang, H., Menzies, K. J., Williams, E. G., Mouchiroud, L., Moullan, N., Hagberg, C., Li, W., Timmers, S., Imhof, R., Verbeek, J., Pujol, A., van Loon, B., Viscomi, C., Zeviani, M., Schrauwen, P., Sauve, A. A., Schoonjans, K., & Auwerx, J.
- Affiliations
- University of Helsinki (FI)
- École Polytechnique Fédérale de Lausanne (CH)
- Karolinska Institutet (SE)
- Weill Cornell Medicine (US)
- Maastricht University Medical Centre (NL)
- University of Zurich (CH)
- Universitair Ziekenhuis Leuven (BE)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Corresponding author
- Cantó, Carles
- Auwerx, Johan
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 19
- Issue
- 6
- Pages
- 1034-1041
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4047186
- OpenAlex
- W2043299439
- Semantic Scholar
- 22c0ab8ac3ea07ea627e93272d408ed3065096f6
- Cited by
- 254
- References
- 41
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 15 · 2023: 23 · 2022: 16 · 2021: 22 · 2020: 31 · 2019: 23 · 2018: 18 · 2017: 28 · 2016: 27 · 2015: 22 · 2014: 10
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Radboud Repository (Radboud University) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125487, 31003A, 124713)
- Suomen Kulttuurirahasto
- Saastamoisen säätiö
- National Institutes of Health
- Health Science Center, University of Tennessee (R01AG043930)
- National Institute on Aging (R01AG043930)
- National Heart, Lung, and Blood Institute (R01HL106511-01A, R01HL106511)
- National Institute of General Medical Sciences (R01GM106072)
- FP7 Ideas: European Research Council (322424)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- PARP1, PARP inhibitors, mitochondrial function, skeletal muscle, energy expenditure, mitochondrial dysfunction, obesity, exercise fitness, myotubes, Caenorhabditis elegans, metabolic homeostasis
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Benzamides, Benzimidazoles, Cells, Cultured, Energy Metabolism, Enzyme Inhibitors, Humans, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerases, Caenorhabditis elegans, Mice, Knockout, Muscle Fibers, Skeletal, Mice, Sirtuin 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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