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Cited by 254Mitochondrial Function and PathologyMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle

Open access
Pirinen, Eija, Cantó, Carles, Jo, Young Suk, Morato, Laia, Zhang, Hongbo, Menzies, Keir J., Williams, Evan G., Mouchiroud, Laurent +14 more·2014·Cell Metabolism
DOI 10.1016/j.cmet.2014.04.002PMC PMC4047186
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Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2014.04.002

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Prolonged PARP inhibitor treatment improves physical fitness in mice.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    VO2max was significantly higher with MRL-45696.

    “Maximal O2 consumption capacity (VO2max), which critically determines endurance performance, was significantly higher with MRL-45696 (Figure S3D).”
    Quote in the paperSubstantial claim
  • Findingown data

    Intracellular NAD+ content was higher in muscle from MRL-45696-treated mice.

    “In line with PARP inhibition, intracellular NAD+ content was higher in muscle from treated mice (Figure 1I).”
    Quote in the paperSubstantial claim
  • Findingown data

    Parp-1 expression shows a strong inverse relationship with energy expenditure in genetically diverse mouse populations.

    “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).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Parp-1 expression levels in skeletal muscle serve as a proxy for PARP-1 activity.
  • Findingown data

    PARP inhibitors lessen genetic mitochondrial metabolism defects in C. elegans.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mouchiroud et al., 2013 source

      Not checked in the free run.

    • Rests on an assumption: C. elegans mev-1 mutants are a valid model for genetic mitochondrial defects in humans.
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    MRL-45696 was linked to higher energy expenditure without altering activity or food intake.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lower PARP activity led to SIRT1 activation, shown by reduced FOXO1 acetylation despite slightly lower SIRT1 levels.

    “Reductions in PARP activity translated also into SIRT1 activation, as reflected by lower FOXO1 acetylation, despite slightly lowered SIRT1 levels (Figure 1K).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among the tested Paribs, MRL-45696 was the most effective at rescuing H2O2-induced NAD+ decline, with a low nanomolar IC50.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Chinnaiyan et al., 2012

      Not checked in the free run.

    • cites Jones et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    MRL-45696 raised mitochondrial membrane potential and O2 consumption rates at 10nM.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MRL-45696 and AZD-2281 were not toxic at these concentrations, since ATP content did not change.

    “Notably, MRL-45696 or AZD-2281 were not toxic at these concentrations, as ATP content was unaffected (Figures S1D and S1H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No signs of genomic DNA toxicity or cellular damage appeared in MRL-45696-treated mice; liver 8-oxo-dG and muscle lipid peroxidation were similar across groups.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AZD-2281 lowered redox potential and raised MMP and OCR at nanomolar concentrations.

    “In agreement, nanomolar concentrations of AZD-2281 decreased redox potential, while increasing MMP and OCR (Figures S1E–S1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The rise in NAD+ was confined to nuclear and/or cytosolic compartments, while mitochondrial NAD+ remained similar between groups.

    “The higher NAD+ levels were restricted to the nuclear and/or cytosolic compartments, since mitochondrial NAD+ content was similar between both groups (Figure 1J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MRL-45696 lowered total PARP activity in skeletal muscle by 50% and in other tissues including brain and liver.

    “MRL-45696 reduced total PARP activity in skeletal muscle (−50%; Figure 1H) and in others tissues tested, including brain and liver (Figure S2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MRL-45696 prevented H2O2-induced PARP activation and raised NAD+ in NDUFS1 mutant fibroblasts.

    “MRL-45696 efficiently prevented H2O2-induced PARP activation (Figure 4F) and increased NAD+ (Figure 4G) in NDUFS1 mutant fibroblasts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MRL-45696 effectively inhibited PARP activity and OCR in mev-1 mutants.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mouchiroud et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Sirt1, Tfam and c-myc expression increased in Parib-treated muscles.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gomes et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    MRL-45696 gave primary myotubes from obese patients a greater capacity to oxidize lipids, probably by improving mitochondrial function, as indicated by higher CS activity.

    “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).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Primary myotubes from obese patients are a valid model for skeletal muscle mitochondrial function in obese humans.

  • May combine two claims.

    Findingown data

    MRL-45696 increased OCR, lipid oxidation and CS activity in NDUFS1 mutant fibroblasts.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MRL-45696 raised mitochondrial complex abundance without changing their mobility.

    “MRL-45696 increased the abundance of mitochondrial complexes, but did not change their mobility (Figure 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    MRL-45696 blocked PARP activation, raised NAD+ levels and stimulated OCR in primary myotubes from obese patients.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Timmers et al., 2012

      Not checked in the free run.

    • Rests on an assumption: Primary myotubes from obese patients are a valid model for skeletal muscle mitochondrial function in obese humans.

  • May combine two claims.

    Findingown data

    MRL-45696 increased slow oxidative MHCI and reduced MHCIIb levels.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Paribs could not enhance endurance, respiratory capacity or CS activity in SIRT1skm−/− mice.

    “Interestingly, Paribs were unable to enhance endurance, respiratory capacity and CS activity in the SIRT1skm−/− mice (Figures 2A–2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Parp-1 expression was positively correlated with body weight, Tnnc2 and Tnni2.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Endurance or VO2max was not impaired in SIRT1skm−/− mice.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Menzies et al., 2013

      Not checked in the free run.

    • cites Philp et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The increased respiration prevented age-related physiological decline, as old mev-1 mutants kept youthful motility.

    “The increased respiration also translated into effective prevention against age-related physiological decline, as old mev-1 mutants maintained youthful motility (Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Parp-1 expression in BXD muscles was inversely correlated with night VO2, VO2max improvement after 10 days training, and Tnni1 expression.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Marked metabolic effects occurred, including improved mitochondrial function and protection against diet-induced obesity.

    “In contrast, marked metabolic effects were observed, such as improved mitochondrial function and protection against diet-induced obesity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Deleting the Parp-1 gene in mice boosts oxidative metabolism and guards against obesity caused by diet.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bai et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle mitochondrial oxidative capacity is higher in Parp-1−/− mice, which protects them from insulin resistance caused by high-fat diet.

    “As a consequence, mitochondrial oxidative capacity is enhanced in muscle of Parp-1−/− mice, protecting them against high-fat diet (HFD)-induced insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bai et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Removing Parp-1 increases NAD+ availability and SIRT1 activity in skeletal muscle and brown adipose tissue.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bai et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    This work prepares the ground for potential clinical use of Paribs when mitochondrial function is defective.

    “Therefore, our work sets the stage for the possible clinical use of Paribs in situations of defective mitochondrial function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sirtuin enzymes act as key regulators of mitochondrial and oxidative metabolism.

    “The sirtuin enzymes have emerged as critical regulators of mitochondrial and oxidative metabolism (Chalkiadaki and Guarente, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chalkiadaki and Guarente, 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss of mitochondrial number and activity characterizes several inherited mitochondrial diseases and age-related neurodegenerative and metabolic disorders.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Andreux et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PARP inhibitors are available and are being tested clinically in cancer.

    “PARP inhibitors (Paribs) already exist and are clinically tested in the cancer field (Curtin and Szabo, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Curtin and Szabo, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    MRL-45696 has strong effects on mitochondrial translation that end in UPRmt induction.

    “Altogether, these results illustrate the robust effects of MRL-45696 on mitochondrial translation, which culminate in the induction of UPRmt.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mev-1 mutants, complex II electron transport from succinate to ubiquinone is impaired, causing higher superoxide levels and premature aging.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Senoo-Matsuda et al., 2001 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Paribs raise mitochondrial respiratory capacity in worms by triggering UPRmt in a SIRT1-dependent way.

    “Paribs increase mitochondrial respiratory capacity in worms by triggering the mitochondrial unfolded protein response (UPRmt-) in a SIRT1-dependent manner (Mouchiroud et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mouchiroud et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Earlier results indicated PARP activity rises with high-fat diet, likely favoring fat storage over burning.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bai et al., 2011 source

      Not checked in the free run.

    • cites Erener et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The success of Paribs is thought to depend on cancer cells' high reliance on PARP enzymes for DNA repair, but may also involve reprogramming cells toward oxidative metabolism.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Curtin and Szabo, 2013 source

      Not checked in the free run.

    • cites Bai et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PARPs silence translation under stress by binding and/or PARylating RNA-binding proteins that control mRNA polyadenylation and protein translation rates.

    “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)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Luo and Kraus, 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Paribs are currently tested for oncology indications, with positive results in tumors that have defective homologous DNA recombination repair.

    “Paribs are currently being tested for oncology indications, with positive outcomes in tumors with dysfunctional homologous DNA recombination repair (Curtin and Szabo, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Curtin and Szabo, 2013 source

      Not checked in the free run.

37 of 37

  • 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).”
4 of 4

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?

  • Pharmacological inhibition of poly (ADP-ribose) polymerase in mice activates SIRT1 and increases mitochondrial respiratory capacity, leading to augmented fitness and protection from diet-induced obesity.

    “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]

  • Poly (ADP-ribose) polymerase inhibition rescued mitochondrial respiration defects and increased FAO in myotubes from obese patients by augmenting mitochondrial function.

    “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.

  • Citrate synthase result names a different compound

    Minor

    The muscle experiment is described as treatment with MRL-45696, but its citrate synthase result is attributed to MRL-45595.

  • Long-term treatment dose has conflicting units

    Minor

    The results give the MRL-45696 dose as 50 mg/kg/day, whereas the long-term animal procedure gives 50 mg/g/kg. These are not the same dosing units.

  • Worm respiration is described as both inhibited and increased

    Minor

    The text says MRL-45696 inhibited oxygen consumption in mev-1 mutants, then describes increased respiration in those mutants as the basis for improved motility.

3 of 3

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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)
DOI
10.1016/j.cmet.2014.04.002
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
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 › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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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