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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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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.
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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: § 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § PARP inhibition enhances endurance and 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § PARP inhibition enhances endurance and mitochondrial function · plain
- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Citrate synthase result names a different compound
MinorThe muscle experiment is described as treatment with MRL-45696, but its citrate synthase result is attributed to MRL-45595.
“These results are consistent with the marked increase in citrate synthase (CS) activity after MRL-45595 (Figure 2C).”
“Despite similar body weight and composition (Figures S3A–S3C), MRL-45696-treated mice ran for a significantly longer distance (Figure 2A).”
Long-term treatment dose has conflicting units
MinorThe 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.
“We next fed HFD admixed with MRL-45696 (50 mg/kg/day) to 10-wk old male C57BL/6J mice.”
“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.”
Worm respiration is described as both inhibited and increased
MinorThe text says MRL-45696 inhibited oxygen consumption in mev-1 mutants, then describes increased respiration in those mutants as the basis for improved motility.
“MRL-45696 effectively inhibited PARP activity (Figure 4C) and OCR in mev-1 mutants (Figure 4D)”
“The increased respiration also translated into effective prevention against age-related physiological decline, as old mev-1 mutants maintained youthful motility (Figure 4E).”
Citations
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Self-citationAMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
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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×
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“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).”
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BackgroundMetabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease
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Self-citationQuantitative Analysis of NAD Synthesis-Breakdown Fluxes
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BackgroundSelf-citationNAD + repletion improves muscle function in muscular dystrophy and counters global PARylation
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“…as PARP-1 or CD38 (Fig 1), can help to preserve NAD + levels for sirtuin activation (Aksoy et al , 2006a; Barbosa et al , 2007; Bai et al , 2011; Pirinen et al , 2014), especially in situations when non-sirtuin NAD + consumers are overactivated (Bai et al , 2011; Braidy et al , 2011; Mouchiroud…”
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“The poly(ADP-ribose) polymerase (PARP) inhibitor; niraparib enhances mitochondrial fatty acid oxidation and helps to alleviate oxidative stress in immune cells (67).”
BackgroundDollerup, O. L., Chubanava, S., Agerholm, M., Søndergård, S. D., Altıntaş, A., Møller, A. B., Høyer, K. F., Ringgaard, S., Stødkilde‐Jørgensen, H., Lavery, G. G., et al. (2020) · The Journal of Physiology · doi:10.1113/jp278752 · Cited by 145
“…of boosting NAD+ metabolism, including NMN supplementation and pharmacological inhibition of the NAD+-consuming PARP1 enzyme (Bai et al. 2011; Pirinen et al. 2014), ameliorate mitochondrial dysfunction in the skeletal muscle of mice (Gomes et al. 2013; Mills et al. 2016; Uddin et al. 2016).”
BackgroundNew Facets in the Regulation of Gene Expression by ADP-Ribosylation and Poly(ADP-ribose) Polymerases
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“Chronic treatment with PARP inhibitors increased NAD + levels and mitochondrial respiration in 10-week-old mice and triggered UPR mt and increased mitochondrial respiration and lifespan in worms 109,257 .”
van de Weijer, T., Phielix, E., Bilet, L., Williams, E. G., Ropelle, E. R., Bierwagen, A., Livingstone, R., Nowotny, P., Sparks, L. M., Paglialunga, S., et al. (2015) · Diabetes · doi:10.2337/db14-0667 · Cited by 139
“Most striking was the observation that Acipimox induced a gene expression signature that was similar to the signature that we observed previously when animals were treated long term with the NAD boosters, such a NR (13) or PARP inhibitors (27; 35).”
BackgroundSelf-citationOxidative Stress in Stem Cell Aging
Chen, F., Liu, Y., Wong, N.-K., Xiao, J., & So, K. (2017) · Cell Transplantation · doi:10.1177/0963689717735407 · Cited by 138
“Previous studies have shown that supplementation of NADþ increased the longevity.(19,20) Recently, it was demonstrated that NADþ acts as a pivotal switch to modulate senescence of muscle stem cells through the mitochondrial unfolded protein response and the synthesis of prohibitin proteins.”
BackgroundThe mitochondrial unfolded protein response–synchronizing genomes
Jovaisaite, V., & Auwerx, J. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.12.003 · Cited by 131
Lin, Y., & Haynes, C. M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.004 · Cited by 128
“and worms have shown that NAD is reduced in aged tissues such as muscle (Cantó et al., 2015; Pirinen et al., 2014), as well as in livers of mice fed a high-fat and high-sugar diet (Gariani et al.”
Fletcher, R. S., Ratajczak, J., Doig, C. L., Oakey, L. A., Callingham, R., Xavier, G. D. S., Garten, A., Elhassan, Y., Redpath, P., Migaud, M. E., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.05.011 · Cited by 125
Self-citationPoly(ADP-ribose) polymerases as modulators of mitochondrial activity
Bai, P., Nagy, L., Fodor, T., Liaudet, L., & Pacher, P. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.11.003 · Cited by 120
Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease
Lee, C. F., Caudal, A., Abell, L., Gowda, G. A. N., & Tian, R. (2019) · Scientific Reports · doi:10.1038/s41598-019-39419-4 · Cited by 128
Loss of the RNA polymerase III repressor MAF1 confers obesity resistancePreprint
Bonhoure, N., Byrnes, A., Moir, R. D., Hodroj, W., Preitner, F., Praz, V., Marcelin, G., Chua, S. C., Martínez-López, N., Singh, R., et al. (2015) · Genes & Development · doi:10.1101/gad.258350.115 · Cited by 119
“Multiple genetic and pharmacological interventions that raise the level of NAD are known to enhance oxidative metabolism and provide protection against diet-induced obesity (Bai et al. 2011; Cantó et al. 2012; Pirinen et al. 2014).”
BackgroundSelf-citationUpdate on mitochondria and muscle aging: All wrong roads lead to sarcopenia
Picca, A., Calvani, R., Bossola, M., Allocca, E., Menghi, A., Pesce, V., Lezza, A. M. S., Bernabei, R., Landi, F., & Marzetti, E. (2018) · Biological Chemistry · doi:10.1515/hsz-2017-0331 · Cited by 116
“Moreover, boosting NAD+ levels with poly (ADP-ribose) polymerase (PARP) inhibitors is protective against muscle dysfunction induced by mitochondrial dysfunction (Pirinen et al., 2014).”
BackgroundMitochondrial unfolded protein response: An emerging pathway in human diseases
Zhu, L., Zhou, Q., He, L., & Chen, L. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.013 · Cited by 118
Henstridge, D. C., Whitham, M., & Febbraio, M. A. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.08.003 · Cited by 112
Hocsák, E., Szabó, V., Kálmán, N., Antus, C., Cseh, A. M., Sümegi, K., Erős, K., Hegedüs, Z., Gallyas, F., Sümegi, B., et al. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.04.018 · Cited by 111
Emerging concepts in the therapy of mitochondrial disease
Viscomi, C. F., Bottani, E., & Zeviani, M. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.03.001 · Cited by 109
Self-citationRegulation of Glucose Metabolism by NAD+ and ADP-Ribosylation
Hopp, A.-K., Grüter, P., & Hottiger, M. O. (2019) · Cells · doi:10.3390/cells8080890 · Cited by 108
“Further, ARTD2-deficient animals were protected against diet-induced obesity [179].”
BackgroundUncoupling of PARP1 trapping and inhibition using selective PARP1 degradation
Wang, S., Han, L., Han, J., Li, P., Ding, Q., Zhang, Q.-J., Liu, Z., Chen, C., & Yu, Y. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0379-2 · Cited by 104
The taming of PARP1 and its impact on NAD+ metabolism
Hurtado-Bagès, S., Knobloch, G., Ladurner, A. G., & Buschbeck, M. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.01.014 · Cited by 112
“The Auwerx Lab showed an indirect effect on respiration exerted by increased NADþ-dependent SIRT1 activity in the nucleus that is mediated by the upregulation of genes promoting respiration [59,62].”
BackgroundJokinen, R., Pirnes-Karhu, S., Pietiläinen, K. H., & Pirinen, E. (2017) · Redox Biology · doi:10.1016/j.redox.2017.02.011 · Cited by 103
Self-citationThe complex crosstalk between mitochondria and the nucleus: What goes in between?
Cagin, U., & Enrı́quez, J. A. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.01.026 · Cited by 107
Integrating the Hallmarks of Aging Throughout the Tree of Life: A Focus on Mitochondrial Dysfunction
van der Rijt, S., Molenaars, M., McIntyre, R. L., Janssens, G. E., & Houtkooper, R. H. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.594416 · Cited by 102
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Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule
Elhassan, Y., Philp, A., & Lavery, G. G. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2017-00092 · Cited by 93
Yasuda, I., Hasegawa, K., Sakamaki, Y., Muraoka, H., Kawaguchi, T., Kusahana, E., Ono, T., Kanda, T., Tokuyama, H., Wakino, S., et al. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020081188 · Cited by 92
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“Upon pathological stimulus, the hyperactivation of PARP‐1 may initiate caspase‐independent cell damages with energetic depletion, mitochondrial dysfunction, and β‐ oxidation impairments (Canto & Auwerx, 2012; Pirinen et al., 2014).”
BackgroundWang, D., Yang, Y., Zou, X., Zhang, J., Zheng, Z., & Wang, Z. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa214 · Cited by 87
“Quantification of mtDNA was performed by use of the ratio of a mitochondrial gene (16S RNA) to a nuclear gene (UCP2) as described (24).”
MethodSzántó, M., & Bai, P. (2020) · Genes & Development · doi:10.1101/gad.334284.119 · Cited by 91
“…studies that reported a lean phenotype, an energy expenditure phenotypewas described due tomitochondrial biogenesis in the brown adipose tissue and the skeletal muscle, attributed mainly to the activation of the NAD+– SIRT1 axis (Bai et al. 2011b; Pirinen et al. 2014; Lehmann et al. 2015).”
BackgroundThe CD38 glycohydrolase and the NAD sink: implications for pathological conditions
Zeidler, J. D., Hogan, K. A., Agorrody, G., Peclat, T., Kashyap, S., Kanamori, K. S., Gomez, L. S., Mazdeh, D. Z., Warner, G. M., Thompson, K. L., et al. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00451.2021 · Cited by 95
Bottani, E., Lamperti, C., Prigione, A., Tiranti, V., Persico, N., & Brunetti, D. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12111083 · Cited by 89
“Various approaches can increase intracellular NAD+ concentrations, including (I) supplementation with NAD+ precursor [99,100]; (II) pharmacological inhibition of poly (ADP) ribosyl polymerase 1 (Parp1), an NAD+ consumer, and SIRT1 competitor [101,102]; or (III) by inhibition of aminocarboxymuconate semialdehyde decarb…”
MethodMondrinos, M. J., Alisafaei, F., Yi, A. Y., Ahmadzadeh, H., Lee, I., Blundell, C., Seo, J., Osborn, M., Jeon, T., Kim, S. M., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe9446 · Cited by 86
Ground control to major TOM: mitochondria–nucleus communication
Eisenberg‐Bord, M., & Schuldiner, M. (2016) · FEBS Journal · doi:10.1111/febs.13778 · Cited by 80
New directions in poly(ADP‐ribose) polymerase biology
Bock, F. J., & Chang, P. (2016) · FEBS Journal · doi:10.1111/febs.13737 · Cited by 78
Rappou, E., Jukarainen, S., Rinnankoski‐Tuikka, R., Kaye, S. M., Heinonen, S., Hakkarainen, A., Lundbom, J., Lundbom, N. M. I., Saunavaara, V., Rissanen, A., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3054 · Cited by 79
“Deletion of Parp1 and Parp2 genes (6, 17) and pharmacological PARP inhibition (18) mitigate HFD-induced obesity and increase insulin sensitivity.”
BackgroundSelf-citationBST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities
Yaku, K., Palikhe, S., Izumi, H., Yoshida, T., Hikosaka, K., Hayat, F., Karim, M., Iqbal, T., Nitta, Y., Sato, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27080-3 · Cited by 76
Targeting metabolism in cellular senescence, a role for intervention
Nacarelli, T., & Sell, C. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.08.049 · Cited by 79
NAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health
Campagna, R., & Vignini, A. (2023) · Antioxidants · doi:10.3390/antiox12020376 · Cited by 76
“Thus, both glycolysis and the TCA cycle can affect the NAD+ homeostasis by modifying the NAD+ and NADH contents in the cytoplasm and the nucleus, respectively [25].”
BackgroundZumla, A. I., Rao, M., Dodoo, E., & Maeurer, M. J. (2016) · BMC Medicine · doi:10.1186/s12916-016-0635-1 · Cited by 73
“Niraparib PARP inhibitor Ovarian and breast cancers Inhibits PARP1/2 to cause double strand DNA breaks in cells, abrogating proliferation; niraparib has been shown to restore mitochondrial respiration in human muscle fibres, likely by improving FAO, thus promoting maintenance of anti-TB memory CD8 T cells [131]”
BackgroundStoyas, C. A., Bushart, D. D., Switonski, P. M., Ward, J. M., Alaghatta, A., Tang, M., Niu, C., Wadhwa, M., Huang, H., Savchenko, A., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.11.019 · Cited by 69
“Indeed, previous studies have shown that decreased PARP1 activity, due to genetic reduction or chemical inhibition, yielded a marked increase in NAD+ levels accompanied by enhanced Sirt1 activity (Bai et al., 2011; Pirinen et al., 2014), indicating that PARP1 and Sirt1 compete for NAD+ in the nucleus.”
BackgroundSelf-citationLehmann, S., Costa, A. C., Celardo, I., Loh, S. H. Y., & Martins, L. M. (2016) · Cell Death & Disease · doi:10.1038/cddis.2016.72 · Cited by 69
NAD+ regulates nucleotide metabolism and genomic DNA replication
Munk, S. H. N., Merchut‐Maya, J. M., Adelantado-Rubio, A., Hall, A., Pappas, G. D., Milletti, G., Lee, M., Johnsen, L. G., Guldberg, P., Bártek, J., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01280-z · Cited by 74
Metabolic roles of poly(ADP-ribose) polymerases
Vida, A., Márton, J., Mikó, E., & Bai, P. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.12.009 · Cited by 69
Martire, S., Fuso, A., Mosca, L., Forte, E., Correani, V., Fontana, M., Scarpa, S., Maras, B., & D’Erme, M. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151040 · Cited by 64
“Furthermore, PARP-1 inhibition produced an enhancement of mitochondrial activity in muscle and brown adipose tissue [30, 69] and enhanced fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity [70].”
MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
Marjanović, M. P., Hurtado-Bagès, S., Lassi, M., Valero, V., Malinverni, R., Delage, H., Navarro, M., Corujo, D., Guberović, I., Douet, J., et al. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3481 · Cited by 64
The balance between NAD+ biosynthesis and consumption in ageing
Strømland, Ø., Diab, J., Ferrario, E., Sverkeli, L. J., & Ziegler, M. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111569 · Cited by 64
“Notably, PARP1 inhibitors boost NAD levels and increase SIRT1 activity and restore mitochondrial fitness and function [93].”
NAD+ metabolism as a target for metabolic health: have we found the silver bullet?
Connell, N. J., Houtkooper, R. H., & Schrauwen, P. (2019) · Diabetologia · doi:10.1007/s00125-019-4831-3 · Cited by 60
Self-citationResveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3
Mathieu, L., Costa, A. L., Bachelier, C. L., Slama, A., Lèbre, A.-S., Taylor, R. W., Bastin, J., & Djouadi, F. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.027 · Cited by 61
PARP inhibition in platinum-based chemotherapy: Chemopotentiation and neuroprotection
McQuade, R. M., Stojanovska, V., Bornstein, J. C., & Nurgali, K. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.09.031 · Cited by 59
Cordeiro, A. V., Brícola, R. S., Braga, R. R., Lenhare, L., Silva, V. R. R., Anaruma, C. P., Katashima, C. K., Crisol, B., Simabuco, F. M., da Silva, A. S. R., et al. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa059 · Cited by 54
Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity
Brady, P. N., Goel, A., & Johnson, M. A. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00038-18 · Cited by 58
“In contrast, PARP inhibition increases NAD levels (275, 298) and protects against obesity (275, 298, 299).”
BackgroundThe secret messages between mitochondria and nucleus in muscle cell biology
Soledad, R. B., Charles, S., & Das, S. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.03.019 · Cited by 54
Sarcopenia in aging, obesity, and cancer
Ligibel, J. A., Schmitz, K. H., & Berger, N. A. (2020) · Translational Cancer Research · doi:10.21037/tcr-2019-eaoc-05 · Cited by 60
“By preserving NAD+ pools, PARP inhibitors, commonly used in chemotherapy, can improve mitochondrial metabolism, which may preserve muscle mass (34-40).”
BackgroundGenome Instability and DNA Repair in Somatic and Reproductive Aging
Panier, S., Wang, S., & Schumacher, B. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-093128 · Cited by 64
Erlich, A. T., Tryon, L. D., Crilly, M. J., Memme, J. M., Moosavi, Z. S. M., Oliveira, A. N., Beyfuss, K. A., & Hood, D. A. (2016) · Integrative Medicine Research · doi:10.1016/j.imr.2016.05.003 · Cited by 59
Wang, X., Zhang, Z.-F., Zheng, G., Wang, A., Sun, C., Qin, S., Zhuang, J., Lu, J. L., Ma, D., & Zheng, Y. (2017) · Molecules · doi:10.3390/molecules22081315 · Cited by 55
“It has been well demonstrated that the protein expression of NAMPT is decreased, while the level of PARP1 is increased during HFD feeding and obesity, which leads to NAD+ depletion [21,22].”
BackgroundItem, F., Wueest, S., Lemos, V., Stein, S., Lucchini, F. C., Denzler, R., Fisser, M. C., Challa, T. D., Pirinen, E., Kim, Y., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00566-9 · Cited by 54
Self-citationHegedűs, C., Boros, G., Fidrus, E., Kis, G. N., Antal, M., Juhász, T., Janka, E. A., Jankó, L., Paragh, G., Emri, G., et al. (2019) · Cancers · doi:10.3390/cancers12010005 · Cited by 51
“Pharmacological inhibition or deletion of PARP1 and PARP2 improves mitochondrial function and protects against mitochondrial [36,37], metabolic [34], and neurological diseases [38].”
BackgroundRole of PARP-1 in mitochondrial homeostasis
Kadam, A. A., Jubin, T., Roychowdhury, R., & Begum, R. (2020) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2020.129669 · Cited by 55
Cancer-Associated Muscle Wasting—Candidate Mechanisms and Molecular Pathways
Armstrong, V., Fitzgerald, L. W., & Bathe, O. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239268 · Cited by 53
Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia
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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
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