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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
Cites
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Self-citationAMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., & Auwerx, J. (2009) · Nature · doi:10.1038/nature07813 · Cited by 3,300
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“Notably, Paribs are in general well tolerated by patients, with few reported side effects (Audeh et al., 2010; Bundred et al., 2013; Tutt et al., 2010).”
BackgroundSirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · cited 1×
“The sirtuin enzymes have emerged as critical regulators of mitochondrial and oxidative metabolism (Houtkooper et al., 2012).”
BackgroundSelf-citationSUnSET, a nonradioactive method to monitor protein synthesis
Schmidt, E. K., Clavarino, G., Ceppi, M., & Pierre, P. (2009) · Nature Methods · doi:10.1038/nmeth.1314 · Cited by 1,706
SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation
Hirschey, M. D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D. B., Grueter, C. A., Harris, C., Biddinger, S., Ilkayeva, O. R., et al. (2010) · Nature · doi:10.1038/nature08778 · Cited by 1,687
Tutt, A., Robson, M., Garber, J. E., Domchek, S. M., Audeh, M. W., Weitzel, J. N., Friedlander, M., Arun, B., Loman, N., Schmutzler, R. K., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60892-6 · Cited by 1,655 · cited 2×
“Within the time frameof this study, and in linewith findings inParp-1 / mice (Bai et al., 2011) and in patients treatedwithOlaparib (Audehet al., 2010; Bundred et al., 2013; Tutt et al., 2010), no toxicity or genomic instability was seen in MRL-45696-treated mice.”
BackgroundResultGomes, A. P., Price, N. L., Ling, A. J. Y., Moslehi, J. J., Montgomery, M. K., Rajman, L., White, J. P., Teodoro, J. S., Wrann, C. D., Hubbard, B. P., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.037 · Cited by 1,482 · cited 2×
“Of note, the expression of Sirt1, Tfam, and c-mycwas also increased in Parib-treated muscles (Figure S3K), which indicates that a recently identified SIRT1-dependent pathway (Gomes et al., 2013) by which NAD+ controls metabolic health might also be at play.”
BackgroundMouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.016 · Cited by 1,210 · cited 5×
“MRL-45696 Enhances Mitochondrial Protein Translation and Triggers the UPR Paribs increase mitochondrial respiratory capacity in worms by triggering the mitochondrial unfolded protein response (UPR) in a SIRT1-dependent manner (Mouchiroud et al., 2013).”
BackgroundResultInfluentialSelf-citationOrganelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts
Frezza, C., Cipolat, S., & Scorrano, L. (2007) · Nature Protocols · doi:10.1038/nprot.2006.478 · Cited by 1,188
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Items 101–200 of 252
Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032959 · Cited by 56
ARTD1-induced poly-ADP-ribose formation enhances PPARγ ligand binding and co-factor exchange
Lehmann, M., Pirinen, E., Mirsaidi, A., Kunze, F. A., Richards, P. J., Auwerx, J. H., & Hottiger, M. O. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1260 · Cited by 55
Self-citationWang, X., He, H., Xiong, X., Zhou, S., Wang, W., Feng, L., Han, R., & Xie, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.668491 · Cited by 56
NAD+ metabolism-based immunoregulation and therapeutic potential
Fang, J., Chen, W., Hou, P., Liu, Z., Zuo, M., Liu, S., Feng, C., Han, Y., Li, P., Shi, Y., et al. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01031-5 · Cited by 55
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“These notions are consistent with a recent report of Pirinen and colleagues [53], demonstrating that in vivo, treatment of mice with PARP-1 in cells after siRNA silencing of PARP-1, compared to control as calculated by unpaired t-test (*p<0.”
ResultNAD+: A key metabolic regulator with great therapeutic potential
Sultani, G., Samsudeen, A., Osborne, B., & Turner, N. A. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12508 · Cited by 54
Vatner, D. E., Zhang, J., Oydanich, M. K., Guers, J. J., Katsyuba, E., Yan, L., Sinclair, D. A., Auwerx, J. H., & Vatner, S. F. (2018) · Aging Cell · doi:10.1111/acel.12751 · Cited by 48
Self-citationA New Vision of Mitochondrial Unfolded Protein Response to the Sirtuin Family
Weng, H., Ma, Y., Chen, L., Cai, G., Chen, Z., Zhang, S., & Ye, Q. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200123165002 · Cited by 51
“In conclusion, both in vivo and in vitro experiments have confirmed the interaction between SIRT1 and MRPS5 and the critical role of SIRT1 in the regulation of MRPS5 function.”
BackgroundInfluentialCordeiro, A. V., Peruca, G. F., Braga, R. R., Brícola, R. S., Lenhare, L., Silva, V. R. R., Anaruma, C. P., Katashima, C. K., Crisol, B., Barbosa, L. T., et al. (2020) · GeroScience · doi:10.1007/s11357-020-00246-5 · Cited by 46
Pencina, K. M., Valderrábano, R. J., Wipper, B., Orkaby, A. R., Reid, K. F., Storer, T. W., Lin, A. P., Merugumala, S. K., Wilson, L. A., Latham, N. K., et al. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad027 · Cited by 48
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Intracellular to Interorgan Mitochondrial Communication in Striated Muscle in Health and Disease
Boardman, N. T., Trani, G., Scalabrin, M., Romanello, V., & Wüst, R. C. I. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad004 · Cited by 51
Espinoza‐Derout, J., Shao, X. M., Bankole, E., Hasan, K. M., Mtume, N., Liu, Y., Sinha‐Hikim, A. P., & Friedman, T. C. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00320 · Cited by 47
“Additionally, PARP1 inhibition provides protection against diet-induced obesity (14).”
BackgroundRuan, Q., Ruan, J., Zhang, W., Qian, F., & Yu, Z. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.08.010 · Cited by 44
NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies
Chen, C., Yan, W., Tao, M., & Fu, Y. (2023) · Antioxidants · doi:10.3390/antiox12061230 · Cited by 44
Park, S. J., Ahmad, F., Um, J.-H., Brown, A. L., Xu, X., Kang, H., Ke, H., Feng, X., Ryall, J. G., Philp, A., et al. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.03.019 · Cited by 46
“Indeed, treatment with NAD+ precursors such as nicotinamide mononucleotide or nicotinamide ribose increase intracellular NAD+ levels and confer metabolic benefits (Canto et al., 2012; Gomes et al., 2013; Mouchiroud et al., 2013; Pirinen et al., 2014; Yoshino et al., 2011).”
BackgroundRegulatory Effects of NAD + Metabolic Pathways on Sirtuin Activity
Zhang, N., & Sauve, A. A. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.012 · Cited by 46
“It was shown that in mouse skeletal muscles, the mitochondrial NAD level was found to be approximately twofold higher than the rest of the cell.(102) Additional studies indicate that mitochondrial NAD concentration are ∼250 μM in cultured HEK293 cells,(37) whereas nuclear NAD concentration might be ∼70 μM,(45,103) and…”
Self-citationTargeting mitochondrial quality control for treating sarcopenia: lessons from physical exercise
Picca, A., Calvani, R., Leeuwenburgh, C., Coelho‐Júnior, H. J., Bernabei, R., Landi, F., & Marzetti, E. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1559827 · Cited by 43
“Moreover, boosting NAD levels by poly (ADP-ribose) polymerase (PARP) inhibitors is protective againstmuscle dysfunction related to mitochondrial dyshomeostasis [37].”
BackgroundMuscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila
Guo, S., Zhang, S., Zhuang, Y., Xie, F., Wang, R., Kong, X., Zhang, Q., Feng, Y., Gao, H., Kong, X., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2213857120 · Cited by 45
“PARP inhibitors reverse mitochondrial defects and attenuate genetic defects of mitochondrial metabolism (18).”
BackgroundNicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns
Bhasin, S., Seals, D. R., Migaud, M. E., Musi, N., & Baur, J. A. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad019 · Cited by 50
Wencel, P. L., Lukiw, W. J., Strosznajder, J. B., & Strosznajder, R. P. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0646-8 · Cited by 43
Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism
Williams, K., Ingerslev, L. R., Bork‐Jensen, J., Wohlwend, M., Hansen, A. N., Small, L., Ribel‐Madsen, R., Astrup, A. V., Pedersen, O. B., Auwerx, J. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16537-6 · Cited by 40
Self-citationGenome-Protecting Compounds as Potential Geroprotectors
Proshkina, E., Shaposhnikov, M. V., & Moskalev, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124484 · Cited by 42
“At the organism level, these changes cause beneficial effects, in particular, protection from diet-induced obesity and enhance fitness [42,54,55].”
BackgroundA systems-approach to NAD+ restoration
Conlon, N. J., & Ford, D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114946 · Cited by 41
Chemical and Physiological Features of Mitochondrial Acylation
Ringel, A. E., Tucker, S. A., & Haigis, M. C. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.023 · Cited by 43
“Physiological NADH levels range from 50 to 100 μM in skeletal muscle, which are far below the millimolar concentrations of NADH required to inhibit SIRT3 and SIRT5 in vitro (Madsen et al., 2016; Pirinen et al., 2014).”
BackgroundStocks, B., & Zierath, J. R. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab038 · Cited by 49
Lightfoot, A. P., Nagaraju, K., McArdle, A., & Cooper, R. G. (2015) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000212 · Cited by 38
Role of PGC-1α in the Mitochondrial NAD+ Pool in Metabolic Diseases
Koh, J., & Kim, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094558 · Cited by 39
“Similarly, treatment with PARP1 and PARP2 inhibitors has been shown to increase muscle mitochondrial function and exercise capacity [101,102].”
BackgroundCurrent Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies
Poljšak, B., Kovač, V., & Milisav, I. (2022) · Antioxidants · doi:10.3390/antiox11091637 · Cited by 42
“NAD+ availability can be elevated by PARPs pharmacological inhibitors (BGB-290, olaparib, rucaparib, veliparib, CEP-9722, E7016, talazoparib, iniparib, niraparib (MK—4827), PJ34, DPQ, 3-aminobenzamide) [70,71] and CD38 inhibitors [72–74], such as flavonoids including epigenin, luteolin, quercetin, kuromanin, luteolini…”
BackgroundFang, M., Fan, Z., Tian, W., Zhao, Y., Li, P., Xu, H., Zhou, B., Zhang, L., Wu, X., & Xu, Y. (2015) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.11.010 · Cited by 35
Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies
Djouadi, F., & Bastin, J. (2019) · Cells · doi:10.3390/cells8040289 · Cited by 36
“In patient fibroblasts, attempts to modulate NAD+/NADH ratio ex vivo were first performed using a PARP-1 inhibitor, MRL-45696, in CI-deficient fibroblasts from a patient with nuclear mutations in the NDUFS1 gene [120].”
MethodNAD+ precursor increases aerobic performance in mice
Crisol, B., Veiga, C. B., Braga, R. R., Lenhare, L., Baptista, I. L., Gaspar, R. C., Muñoz, V. R., Cordeiro, A. V., da Silva, A. S. R., Cintra, D. E., et al. (2019) · European Journal of Nutrition · doi:10.1007/s00394-019-02089-z · Cited by 35
Nuclear receptors and AMPK: can exercise mimetics cure diabetes?
Wall, C. E., Yu, R. T., Atkins, A. R., Downes, M., & Evans, R. M. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0073 · Cited by 32
“Similarly, inhibition of the NAD+-consuming DNA repair enzyme poly (ADP-ribose) polymerase 1 (PARP1) conferred resistance to diet-induced metabolic defects through improvements in mitochondrial function and oxidative metabolism in skeletal muscle (Pirinen et al. 2014).”
PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice
Felici, R., Cavone, L., Lapucci, A., Guasti, D., Bani, D., & Chiarugi, A. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0285-y · Cited by 35
Nicotinamide riboside induces a thermogenic response in lean mice
Crisol, B., Veiga, C. B., Lenhare, L., Braga, R. R., Silva, V. R. R., da Silva, A. S. R., Cintra, D. E., de Moura, L. P., Pauli, J. R., & Ropelle, E. R. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.09.015 · Cited by 31
Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice
Wang, H., Kuusela, S., Rinnankoski‐Tuikka, R., Dumont, V., Bouslama, R., Ramadan, U. A., Waaler, J., Linden, A.-M., Chi, N., Krauss, S. J. K., et al. (2020) · International Journal of Obesity · doi:10.1038/s41366-020-0573-z · Cited by 30
Self-citationTian, H., Liu, S., Ren, J. T., LEE, J. K. W., Wang, R., & Chen, P. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00949 · Cited by 32
C. elegans as a model organism to study female reproductive health
Athar, F., & Templeman, N. M. (2022) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2022.111152 · Cited by 34
Management of Leigh syndrome: Current status and new insights
Chen, L., Cui, Y., Jiang, D., Ma, C. Y., Tse, H., Hwu, W., & Lian, Q. (2017) · Clinical Genetics · doi:10.1111/cge.13139 · Cited by 32
Poljšak, B., Kovač, V., & Milisav, I. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8819627 · Cited by 33
Kuenzler, M., Nuss, K. M. R., Karol, A. A., Schär, M. O., Hottiger, M. O., Raniga, S., Kenkel, D., von Rechenberg, B., & Zumstein, M. A. (2017) · Journal of Shoulder and Elbow Surgery · doi:10.1016/j.jse.2016.11.009 · Cited by 29
PARP and other prospective targets for poisoning cancer cell metabolism
Michels, J., Obrist, F., Castedo, M., Vitale, I., & Kroemer, G. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.08.026 · Cited by 28
NAD metabolism in aging and cancer
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“NAD’s role in oxidative phosphorylation contributes to the molecule’s high mitochondrial concentration.(70) At times of nutritional abundance, the energy producing metabolic balance shifts the ratio of NADþ/ NADH to increase NADH pools.”
BackgroundFelici, R., Lapucci, A., Cavone, L., Pratesi, S., Palmini, R. B., & Chiarugi, A. (2015) · Molecular Pharmacology · doi:10.1124/mol.114.097204 · Cited by 28
Adverse effects of weight loss: Are persistent organic pollutants a potential culprit?
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“[115] Pirinen E, Canto C, Jo YS, Morato L, Zhang H, Menzies KJ, et al.”
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Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions
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Olaparib induces browning of in vitro cultures of human primary white adipocytes
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“In mice fed a high-fat diet (HFD), PARP depletion groups had enhanced NAD + levels, increased SIRT1 activity, and improved mitochondrial function [37,38].”
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“In support of this concept, PARP inhibition is apparently beneficial in a number of muscle dysfunction models [138, 139].”
BackgroundThe MacroH2A1.1 – PARP1 Axis at the Intersection Between Stress Response and Metabolism
Hurtado-Bagès, S., Guberović, I., & Buschbeck, M. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00417 · Cited by 24
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Complementary NAD+ replacement strategies fail to functionally protect dystrophin-deficient muscle
Frederick, D. W., McDougal, A. V., Semenas, M., Vappiani, J., Nuzzo, A., Ulrich, J. C., Becherer, J. D., Preugschat, F., Stewart, E. L., Sévin, D. C., et al. (2020) · Skeletal Muscle · doi:10.1186/s13395-020-00249-y · Cited by 21
“One model suggests that calcium dysregulation, stemming from microtears in the sarcolemma, leads to a burst of genotoxic reactive oxygen species and hyperactivation of NAD-consuming PARPs [25, 26].”
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“For instance, rebalancing of the NAD + /NADH ratio through pharmacological interventions has been shown to improve the fitness of mice carrying mitochondrial defects (Canto et al , 2012; Cerutti et al , 2014; Pirinen et al , 2014).”
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“However, recent data show that prolonged PARPi treatment does not induce genomic instability, at least in mice [8].”
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Scarpelli, M., Todeschini, A., Rinaldi, F., Rota, S., Padovani, A., & Filosto, M. (2014) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2014.09.013 · Cited by 19
Trends in Mitochondrial Therapeutics for Neurological Disease
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“biogenesis with promising results in mitochondrial myopathy models [112-114].”
BackgroundMitochondrial protein import and UPRmt in skeletal muscle remodeling and adaptation
Richards, B. J., Slavin, M. B., Oliveira, A. N., Sanfrancesco, V. C., & Hood, D. A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.01.002 · Cited by 19
Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis
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Herrera‐Marschitz, M., Pérez-Lobos, R., Lespay‐Rebolledo, C., Tapia-Bustos, A., Casanova-Ortiz, E., Morales, P., Valdés, J. L., Bustamante, D., & Cassels, B. K. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9795-9 · Cited by 19
“…permeabilization during the secondary (reperfusion) phase following hypoxic-ischaemic injury (Block and Schwarz 1996; Chen et al. 1998; Pirinen et al. 2014; Olah et al. 2015), in agreement with a pivotal role of extrasynaptic NMDA receptors in the effects elicited during the…”
BackgroundLees, J. G., Gardner, D. K., & Harvey, A. J. (2020) · Stem Cells · doi:10.1002/stem.3152 · Cited by 20
Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase
Gaspar, R. S., Katashima, C. K., Crisol, B., Carneiro, F. S., Sampaio, I. H., Silveira, L. R., da Silva, A. S. R., Cintra, D. E., Pauli, J. R., & Ropelle, E. R. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101816 · Cited by 20
Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise
Dent, J. R., Stocks, B., Campelj, D. G., & Philp, A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.03.022 · Cited by 19
NAD+: An old but promising therapeutic agent for skeletal muscle ageing
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Nurturing longevity through natural compounds: Where do we stand, and where do we go?
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Host-Targeted Therapeutics against Multidrug Resistant Intracellular Staphylococcus aureus
Bravo-Santano, N., Behrends, V., & Letek, M. (2019) · Antibiotics · doi:10.3390/antibiotics8040241 · Cited by 16
“Niraparib PARP inhibitor Mycobacterium tuberculosis [61] Phenylbutyrate Histone deacetylase inhibitor Mycobacterium tuberculosis [62]”
BackgroundExercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics
Samant, V., & Prabhu, A. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123225 · Cited by 15
Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases
Nasuhidehnavi, A., Zarzycka, W., Gorecki, I., Chiao, Y. A., & Lee, C. F. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.07.010 · Cited by 20
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Age Is Just a Number: Progress and Obstacles in the Discovery of New Candidate Drugs for Sarcopenia
Kim, H.-J., Jung, D., & Williams, D. R. (2023) · Cells · doi:10.3390/cells12222608 · Cited by 16
“Improved mitochondrial function was also observed in myotubes derived from obese humans with type 2 diabetes (T2DM) [71].”
Liu, Q., Tang, Q., Liao, L., Li, D., Zhu, W., & Zhao, C. (2022) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2022.03.002 · Cited by 14
“18 a pivotal regulator of cellular homeostasis [85], apoptosis [86], muscle regeneration [87], and adipogenesis [88].”
BackgroundNAD metabolism and the SLC34 family: evidence for a liver-kidney axis regulating inorganic phosphate
Tatsumi, S., Katai, K., Kaneko, I., Segawa, H., & Miyamoto, K. (2018) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2204-2 · Cited by 14
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“PARP1 also regulates SIRT1 activity to influence the balance between mitochondrial and nuclear proteins leading to proteostasis(Pirinen et al., 2014).”
Mitonuclear Communication in Stem Cell Function
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Grx2 Regulates Skeletal Muscle Mitochondrial Structure and Autophagy
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“Identification of Transcript Correlations in the BXD Mouse Tissue Data Sets Using a BXD mouse genetic reference population (Pirinen et al., 2014), skeletal muscle microarray data (AffymetrixMouseGene1.”
MethodSelf-citationEvolution of a histone variant involved in compartmental regulation of NAD metabolism
Guberović, I., Hurtado-Bagès, S., Rivera-Casas, C., Knobloch, G., Malinverni, R., Valero, V., Leger, M. M., García, J., Basquin, J., de Cedrón, M. G., et al. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-021-00692-5 · Cited by 12
Possible role of PAPR-1 in protecting human HaCaT cells against cytotoxicity of SiO2 nanoparticles
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“SIRT1 activation [20,82,86] and reactive species production [95–97] were linked with mitonuclear proteostasis in other models.”
BackgroundImportance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders
Helman, T. J., & Braidy, N. (2022) · Drugs & Aging · doi:10.1007/s40266-022-00989-0 · Cited by 13
“In addition, mitochondrial dysfunction because of disrupted NAD+ homeostasis in cardiac hypertrophy and heart failure has been shown to be reversed through use of NAD+ precursors [105, 129].”
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CEST‐2.2 overexpression alters lipid metabolism and extends longevity of mitochondrial mutants
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Sirtuin activation as a therapeutic approach against inborn errors of metabolism
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“Activating sirtuins can improve the acylation state at various levels and mitochondrial function enhanced mitochondrial biogenesis, and improved energy expenditure (Bai et al 2011; Cerutti et al 2014; Pirinen et al 2014).”
Nanodrug Delivery Systems for Myasthenia Gravis: Advances and Perspectives
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“Increasing the levels of NAD + precursors can also ameliorate the symptoms of acquired muscle dysfunction by activating mitochondrial metabolism [126,127].”
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NAD + depletion is central to placental dysfunction in an inflammatory subclass of preeclampsia
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“Long-term treatment (16 weeks) of control mice with MRL-45696 did not reveal any evidence of toxicity in this time frame (Pirinen et al., 2014).”
Erbs, E., Brasen, C. L., Lund, A. M., & Rasmussen, M. B. (2023) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2023.104698 · Cited by 12
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“treated with PARP inhibitors show an increased abundance of mitochondrial respiratory complexes as well as increased mitochondrial respiratory capacity.(20) Mice with a PARP-1 deletion demonstrate greater mitochondrial content and increased energy expenditure in brown adipose and skeletal muscle as well as protection…”
BackgroundFritzen, A. M., Lundsgaard, A., Jeppesen, J. F., Sjøberg, K. A., Høeg, L. D., Deleuran, H. H., Wojtaszewski, J. F. P., Richter, E. A., & Kiens, B. (2019) · The FASEB Journal · doi:10.1096/fj.201801950r · Cited by 10
Mitochondria in Health and Disease
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Crisol, B., Rocha, M. B., Franco, B., Morelli, A. P., Katashima, C. K., Scylas, J. A., Carneiro, F. S., Braga, R. R., Brícola, R. S., de Azambuja, G., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102135 · Cited by 9
“Furthermore, pharmacological PARP inhibitors reversed mitochondrial defects in primary myotubes of obese humans [16].”
InfluentialLai, S.-Y., Zhu, X., Sun, W.-D., Bi, S.-Z., Zhang, C.-Y., Liu, A., & Li, J.-H. (2025) · Biomolecules · doi:10.3390/biom15050719 · Cited by 10
“PARP inhibition increases NAD + levels, enhances SIRT1 activity, boosts mitochondrial function, and modulates liver cancer [67,68].”
Tan, A., Younis, A. Z., Evans, A., Creighton, J. V., Coveny, C., Boocock, D. J., Sale, C., Lavery, G. G., Coutts, A. S., & Doig, C. L. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01420-2 · Cited by 10
Arnhold, J. (2025) · Biomolecules · doi:10.3390/biom15040547 · Cited by 8
Hu, M., Chen, J., Zhang, Q.-Q., Song, Z., Shaukat, H., & Qin, H. (2022) · Food & Nutrition Research · doi:10.29219/fnr.v66.8231 · Cited by 8
“Considering that ameliorating muscular metabolic abnormalities is one of the effective therapeutic approaches in treating obesity and its related metabolic syndrome (34), we speculated that sesamol alleviated metabolic syndrome under obesity condition by regulating metabolism in the skeletal muscle.”
BackgroundProgress in Research on Antitumor Drugs and Dynamic Changes in Skeletal Muscles
Xu, T., Li, Z., Liu, T., Jiang, C.-H., Zhang, Y., Li, H., Jiang, Y. Y., Zhao, J., Guo, W.-J., Guo, J.-Y., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.893333 · Cited by 9
“Some targeted drugs are associated with sarcopenia, which may affect the efficacy of targeted therapy (Bodine et al., 2001; Antoun et al., 2010; Bai et al., 2011; Ito et al., 2013; Pirinen et al., 2014; Moryoussef et al., 2015; Gyawali et al., 2016; Barreiro and Gea, 2018).”
Background
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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