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Cited by 372Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismMitochondrial Function and Pathology

Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility

Open access
Muoio, Deborah M., Noland, Robert C., Kovalik, Jean-Paul, Seiler, Sarah E., Davies, Michael N., DeBalsi, Karen L., Ilkayeva, Olga R., Stevens, Robert D. +8 more·2012·Cell Metabolism
DOI 10.1016/j.cmet.2012.04.005PMC PMC3348515
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Abstract

The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.

AI snapshot

Written from the paper’s full text.

TL;DR

Muscle-specific deletion of carnitine acetyltransferase (CrAT) in mice impairs glucose tolerance and metabolic flexibility, and CrAT loss in human myocytes and type 2 diabetic muscle supports a role in substrate switching. In a human pilot, L-carnitine supplementation improved HOMA-IR in insulin-resistant older subjects, suggesting CrAT-mediated acetylcarnitine efflux as a therapeutic target.

Key findings

  • Muscle-specific Crat knockout mice (CratM-/-) were glucose intolerant and had blunted insulin-mediated glucose lowering on a low-fat diet, with worsening on high-fat feeding; they also gained more body weight and fat mass on high-fat diet.
  • CrAT deficiency lowered acetylcarnitine levels 37–50% in plasma, skeletal muscle, and heart, and caused accumulation of medium- and long-chain acylcarnitines in skeletal muscle; isolated muscle mitochondria from CratM-/- mice showed 16–18% greater palmitate oxidation and a rightward shift in pyruvate IC50.
  • In primary human myocytes, CrAT knockdown lowered CrAT activity 60%, reduced acetylcarnitine export 47%, doubled oleate oxidation, and decreased glucose uptake 13%; CrAT overexpression increased PDH activity and acetylcarnitine efflux.
  • In a human pilot, six months of L-carnitine increased free carnitine and acetylcarnitine 26% and 54%, respectively, and reduced HOMA-IR 50% in the insulin-resistant subgroup (from 3.9 to 1.8); CrAT mRNA was 80% lower in skeletal muscle from type 2 diabetic patients.

Methods

  • Generated muscle-specific Crat knockout mice using a floxed crat allele and MCK-Cre; assessed glucose/insulin tolerance, indirect calorimetry, acylcarnitine profiling, mitochondrial respiration and PDH activity, and isolated soleus muscle incubations with 13C tracers.
  • Used primary human skeletal myocytes with adenoviral CrAT knockdown or overexpression to measure CrAT activity, acetylcarnitine efflux, oleate oxidation, glucose uptake, PDH activity, and stable-isotope tracing.
  • Conducted a human pilot study in n=14 subjects (age ≥60, BMI 25–35.4, fasting glucose 95–125 mg/dl) given 2 g/day oral L-carnitine for six months; outcomes included serum carnitine/acylcarnitines, muscle biopsy substrate oxidation, and HOMA-IR.

Limitations

  • Stated: the human study is described as a pilot, and the authors call for larger-scale trials; they also note that further studies are necessary to delineate the ultimate energetic fate and function of circulating acetylcarnitine.
  • Evident: the human supplementation protocol as described lacks a placebo or control arm, and the small sample (n=14) with subgroup analysis by HOMA-IR cutoff limits generalizability.
  • Evident: several results are reported as “not shown” (e.g., GSK-3β phosphorylation, PDH-E1a phosphorylation at Ser232/Ser293/Ser300), limiting independent assessment of those findings.

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

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2012.04.005

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 23 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Crat deficiency caused marked accumulation of several medium- and long-chain acylcarnitines in skeletal muscle and to a lesser degree in heart, without affecting plasma levels.

    “crat deficiency provoked marked accumulation of several medium and long chain acylcarnitines in skeletal muscle and to a lesser degree in heart, without affecting plasma levels of these metabolites.”
    Quote in the paperSubstantial claim
  • Findingown data

    On low-fat diet, CratM-/- and control mice gained total body weight and fat pad mass at similar rates between 5 and 20 weeks.

    “Between five and twenty weeks of age CratM-/- mice and control littermates (Cratfl/fl) fed a low fat diet gained total body weight and fat pad mass at similar rates (Figure 2A and 2B)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Isolated skeletal muscle mitochondria from CratM-/- mice have near-complete loss (94-98%) of acyltransferase activity with various short-chain acyl-CoA substrates compared to controls.

    “Figure 1E shows a near-complete loss (94-98%) of acyltransferase activity using various short chain acyl-CoA substrates in isolated mitochondria from skeletal muscle of CratM-/- compared to control littermates (Cratfl/fl).”
    Quote in the paperSubstantial claim
  • Findingown data

    On low-fat diet, CratM-/- mice had higher blood glucose at baseline and throughout IPGTT than controls.

    “despite normal body weight when feeding on the low fat diet, blood glucose levels were higher in the CratM-/-, both at baseline and throughout an intra-peritoneal glucose tolerance test (Figure 2C and S. Figure 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Blood glucose lowering in response to acute insulin bolus was blunted in CratM-/- mice regardless of diet.

    “lowering of blood glucose in response to an acute insulin bolus was blunted in the CratM-/- mice, regardless of diet (Figure 2E and S. Figure 1).”
    Quote in the paperSubstantial claim
  • May combine two claims. 33
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    PDH activity was stimulated 1.8-fold by carnitine in control muscle mitochondria, whereas it was inhibited 33% in crat null mitochondria.

    “direct assessment of PDH activity, which was stimulated 1.8-fold by carnitine in the control group whereas a 33% inhibition occurred in the crat null mitochondria (Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma triglycerides and NEFAs were lower in CratM-/- mice on low-fat diet.

    “Plasma triglycerides (TAG) and non-esterified fatty acids (NEFAs; Figure 2F) were lower in the knockout mice”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tissue and plasma levels of propionylcarnitine (C3) were only partially reduced, and butyrylcarnitine (C4) was elevated in heart of CratM-/- mice.

    “Likewise, tissue and plasma levels of propionylcarnitine (C3), another major product of CrAT, were only partially reduced, and butyrylcarnitine (C4) was actually elevated in the heart.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Muscle-specific Crat knockout mice show loss of CrAT function in skeletal muscle and heart without changes in other tissues.

    “Analysis of crat abundance by qRT-PCR, Western blot and enzymatic activity confirmed loss of function in skeletal muscle and heart without effects on expression or activity in other tissues (Figure 1B-D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With pyruvate as sole carbon source, carnitine increased state 3 respiration 4.3-fold in control mitochondria but had no effect in crat null mitochondria.

    “when this assay was performed with pyruvate as the only carbon source (i.e. omitting malate as an anaplerotic substrate), addition of carnitine increased state 3 respiration 4.3-fold in mitochondria from Cratfl/fl mice, whereas this effect was completely absent in the crat null mitochondria (Figure 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Whole-body indirect calorimetry showed no differences in 24h average RER or energy expenditure between CratM-/- and control mice.

    “Whole body indirect calorimetry did not reveal differences in 24 h average RER or energy expenditure between knockout and control mice (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CrAT overexpression increased production of both glucose- and fatty acid-derived acetylcarnitine but did not affect relative enrichment of [13C], regardless of carbon source.

    “CrAT overexpression increased production of both glucose- and fatty acid-derived acetylcarnitine, but did not affect the relative enrichment of [13C], regardless of the carbon source (S. Figure 5C).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Over 90% of total [13C2]acetylcarnitine produced by control muscles was present in the incubation buffer.

    “over 90% of the total [13C2]acetylcarnitine produced by the Cratfl/fl muscles was present in the incubation buffer (Figure 4H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of differentiated human myotubes with rAd-shCrat decreased mRNA levels 60-80%, lowered CrAT specific activity 60%, and reduced cellular export of acetylcarnitine by 47%.

    “Treatment of differentiated human myotubes with the rAd-shCrat virus decreased mRNA levels 60-80% (not shown), lowered CrAT specific activity 60% and reduced cellular export of acetylcarnitine by 47% (Figure 6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nutrient-induced substrate switching was blunted in the insulin-resistant group and trended toward improvement after L-carnitine therapy.

    “nutrient-induced substrate switching was blunted in the insulin resistant group and trended toward an improvement after L-carnitine therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When all subjects were grouped, in vitro oxidation rates of [1-14C]palmitate and [2-14C]pyruvate to 14CO2 were lower after six months of supplementation, whereas incomplete fat oxidation to ASM was unchanged.

    “When all subjects were grouped together, in vitro oxidation rates of [1-14C]palmitate (Figure 7G) and [2-14C]pyruvate (Figure 7H) to 14CO2 were lower after six months of supplementation, whereas incomplete fat oxidation to ASM was unchanged (not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In control group, [13C2]acetylcarnitine accounted for 63% of total acetylcarnitine efflux, and absolute quantities were 692% of those in buffer from CratM-/- muscles.

    “In the control group, [13C2]acetylcarnitine accounted for 63% of total acetylcarnitine efflux, and absolute quantities were 692% of those measured in the incubation buffer from CratM-/- muscles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Decline in complete fat oxidation was accompanied by enhanced cellular acetylcarnitine efflux and increased PDH activity.

    “The decline in complete fat oxidation was accompanied by enhanced cellular acetylcarnitine efflux and increased PDH activity (Figure 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trends were similar in low and high HOMA groups, although statistical significance was achieved only in the former.

    “The trends were similar in the low and high HOMA groups, although statistical significance was achieved only in the former.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Crat deficiency caused a statistically significant rightward shift in the IC50 of pyruvate, exacerbated by increasing palmitate concentration.

    “crat deficiency resulted in a statistically significant rightward shift in the IC50 of pyruvate, an outcome that was exacerbated by increasing the palmitate concentration (Figures 5C & 5D, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of human myotubes with rAd-Crat caused dose-dependent induction of enzyme activity and progressive decline in complete oxidation of oleate, while acid soluble metabolites were unchanged.

    “treatment of human myotubes with rAd-Crat resulted in a dose-dependent induction of enzyme activity along with a progressive decline in complete oxidation of oleate, whereas production of acid soluble metabolites (an index of incomplete fat oxidation) was unchanged (Figure 6C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Partial loss of Crat activity led to a 2-fold increase in oleate oxidation and a modest but significant 13% decrease in uptake of [3H]-2-deoxy-glucose.

    “This partial loss of Crat activity led to a 2-fold increase in oleate oxidation and a modest but significant 13% decrease in uptake of [3H]-2-deoxy-glucose(Figure 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as PDH.

    “support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    CrAT converts acetyl-CoA to membrane-permeant acetylcarnitine, thereby regulating mitochondrial and intracellular carbon trafficking.

    “By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The high residual activity (54%) with octanoyl-CoA is likely due to carnitine octanoyltransferase and/or CPT2.

    “The high (54%) residual activity with octanoyl-CoA (C8) is likely attributable to carnitine octanoyltransferase and/or palmitoyltransferase 2 (Ramsay and Zammit, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ramsay and Zammit, 2004

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    CrAT plays an essential role in regulating substrate switching and defending whole-body glucose homeostasis.

    “Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance.”
    • Also stated in: § Discussion · boosted
      “Results described herein now provide compelling evidence that CrAT does indeed play an indispensable role in defending whole body glucose homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CrAT provides a way to relieve PDH inhibition during the fasted-to-fed transition, enabling a quicker and more efficient switch from fatty acid to glucose oxidation.

    “We therefore surmise that CrAT affords a mechanism to ease inhibition of PDH during the fasted to fed transition, thereby facilitating a more rapid and efficient transition from fatty acid to glucose oxidation.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    MemCode protein staining was used as a loading control for each blot.

    “MemCode (Pierce, Rockford, IL) protein staining served as a loading control for each blot.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings establish a previously unappreciated role for CrAT in whole-body energy metabolism and suggest it may be useful as a therapeutic target.

    “Although the answers to this and a number of intriguing questions now await future investigation, our findings clearly establish a heretofore unappreciated role for CrAT in controlling whole body energy metabolism and raise promise that this enzyme might have utility as a therapeutic target.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The reverse Randle cycle model holds that glucose and fatty acid oxidation pathways are reciprocally regulated in a tightly coordinated manner.

    “According to this so-called “reverse Randle cycle”, the pathways governing glucose and fatty acid oxidation are reciprocally regulated in a tightly coordinated fashion (Ruderman et al., 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ruderman et al., 1999

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    CrAT's regulatory functions probably extend beyond pyruvate metabolism.

    “Lastly, whereas this investigation highlighted the interplay between acetylcarnitine efflux and PDH activity, the regulatory functions of CrAT are likely to extend beyond pyruvate metabolism.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Acetyl-CoA and other short chain acyl-CoAs act as substrates and allosteric modulators of several metabolic enzymes.

  • Classified as probably not a substantial claim.

    Premisecitation

    Malonyl-CoA inhibits CPT1, limiting mitochondrial fatty acid uptake and oxidation.

    “Malonyl-CoA in turn inhibits CPT1, thus restricting mitochondrial uptake and oxidation of fatty acid (McGarry et al., 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McGarry et al., 1991

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In muscle, carnitine enhances oxidation of both lipids and carbohydrates.

    “Another important and perhaps paradigm-shifting concept that emerges from this work is that carnitine positively regulates both lipid and carbohydrate oxidation in muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In liver, CrAT is absent from the mitochondrial compartment and localized mainly to peroxisomes.

    “in the liver, CrAT is absent from the mitochondrial compartment (S. Figure 3) and is instead localized mainly to the peroxisomes (Beenakkers and Klingenberg, 1964; Bloisi et al., 1990).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Beenakkers and Klingenberg, 1964

      Not checked in the free run.

    • cites Bloisi et al., 1990

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Crat deficiency lowered mitochondrial and tissue efflux of glucose-derived carbons while increasing β-oxidation rates.

    “Thus, crat deficiency lowered mitochondrial and tissue efflux of glucose-derived carbons (Figure 4) while increasing rates of β-oxidation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Acetyl-CoA antagonizes PDH activity through direct allosteric inhibition and by stimulating PDH kinases that phosphorylate and inactivate the E1a catalytic subunit.

    “Acetyl-CoA antagonizes PDH activity through direct allosteric inhibition of the enzyme complex and by stimulating a family of PDH kinases that inactive the E1a catalytic subunit via phosphorylation at multiple serine residues (Sugden and Holness, 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sugden and Holness, 2003

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    L-carnitine's dual actions are mediated by CPT1 and CrAT, which access separate acyl-CoA substrate pools.

    “These dual actions of L-carnitine take effect through CPT1 and CrAT, respectively, which access two discrete pools of acyl-CoA substrates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Crat deficiency resulted in abnormal fuel selection in whole animals and isolated mitochondria, and a corresponding decay in systemic glucose homeostasis.

    “In the current study crat deficiency resulted in abnormal fuel selection, evident in whole animals and in isolated mitochondria, and a corresponding decay in systemic glucose homeostasis.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    Strategies that increase acetylcarnitine efflux might benefit pre-diabetic patients.

    “suggesting that nutritional and/or pharmacological strategies aimed at increasing acetylcarnitine efflux might benefit pre-diabetic patients.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The [13C2]acetylcarnitine detected in crat null muscles could be attributable to residual CrAT activity in whole muscle tissue and/or another acylcarnitine transferase.

    “which could be attributable to residual CrAT activity in whole muscle tissue and/or another acylcarnitine transferase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Together, these results suggest that metabolic disease and/or chronic lipid exposure may impair mitochondrial acetylcarnitine efflux capacity.

    “Taken together, these results suggest that metabolic disease and/or chronic lipid exposure might compromise mitochondrial acetylcarnitine efflux capacity.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Statistical significance was set a priori at p<0.05.

    “Statistical significance was established a priori at p<0.05.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Several studies of early insulin resistance have reported mismatches between physiological changes in insulin-stimulated glucose disposal and activation of the canonical insulin signaling pathway.

    “A number of studies examining the early phases of insulin resistance have likewise reported discrepancies between physiological changes in insulin-stimulated glucose disposal and activation of the canonical insulin signaling pathway (Hoeg et al., 2011; Hoy et al., 2009; Hoy et al., 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hoeg et al., 2011

      Not checked in the free run.

    • cites Hoy et al., 2009

      Not checked in the free run.

    • cites Hoy et al., 2007

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier in vitro work found that long chain acyl-CoAs inhibit CrAT specific activity.

    “and earlier studies reported that CrAT specific activity measured in vitro is inhibited by long chain acyl-CoAs (Chase, 1967).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chase, 1967 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The insulin responsiveness block in these mice seems to occur downstream of Akt or may be independent of insulin signaling.

    “Thus, the block in insulin responsiveness in these mice appears to reside downstream of Akt, or alternatively, might be independent of insulin signaling all together.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    In vitro assays were performed with surplus L-carnitine, implying supplementation replenished mitochondrial free carnitine and/or caused mitochondrial remodelling.

    “these in vitro assays were performed with a surplus of L-carnitine, implying that the supplementation regimen replenished the mitochondrial pool of free carnitine and/or caused mitochondrial remodelling at some other level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These outcomes resembled effects of CrAT overexpression in human myocytes and are consistent with enhanced mitochondrial efflux of acetylcarnitine.

    “These outcomes resembled the effects of CrAT overexpression in human myocytes and are consistent with enhanced mitochondrial efflux of acetylcarnitine.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Reversible protein acetylation is emerging as a central nutrient-sensing mechanism that integrates metabolic control at multiple levels.

    “In addition, reversible protein acetylation is emerging as a central mechanism of nutrient sensing that in turn integrates metabolic control at multiple levels (Hirschey et al., 2009; Schlicker et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hirschey et al., 2009 source

      Not checked in the free run.

    • cites Schlicker et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Muscle-specific ablation of CrAT caused systemic glucose intolerance, interfered with insulin effectiveness, and blunted normal postprandial rise in glucose oxidation.

    “muscle-specific ablation of CrAT caused systemic glucose intolerance, interfered with insulin effectiveness and blunted the normal postprandial rise in glucose oxidation.”
    Quote in the paperSubstantial claim
44 of 44

  • The authors state this as an assumption.

    Muscle is the major source of circulating acetylcarnitine.

    “assuming that muscle is the major source of circulating acetylcarnitine”

  • The authors state this as an assumption.

    Skeletal muscle and heart contribute substantially to the circulating pool of acetylcarnitine.

    “these tissues are presumed to contribute substantially to the circulating pool of acetylcarnitine”

  • The paper relies on this without support.

    The Randle hypothesis holds that acetyl-CoA from glucose and lipid substrates compete for TCA cycle entry, and that increased β-oxidation expands mitochondrial acetyl-CoA, inhibiting PDH and glycolytic flux.

    “The Randle hypothesis predicts that acetyl-CoA molecules derived from glucose and lipid substrates compete for entry into the TCA cycle. When β-oxidation increases, the mitochondrial pool of acetyl-CoA expands and inhibits PDH activity and glycolytic flux.”

  • The paper relies on this without support.

    Chronic L-carnitine supplementation has not been rigorously tested for antidiabetic effects in insulin-resistant humans.

    “Surprisingly, the antidiabetic potential of chronic L-carnitine supplementation has yet to be rigorously tested in insulin resistant humans.”

  • The paper relies on this without support.

    Acetyl-CoA and other short chain acyl-CoAs act as substrates and allosteric modulators of several metabolic enzymes.

    “Acetyl-CoA and other short chain acyl-CoAs serve both as substrates and allosteric modulators of several metabolic enzymes.”
5 of 5

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?

  • l-carnitine supplementation improves metabolic flexibility by decreasing plasma glucose and insulin levels and increasing PDH activity in muscle of insulin-resistant subjects.

    “Although not yet in clinical practice, l-carnitine supplementation improves metabolic flexibility by decreasing plasma glucose and insulin levels and increasing PDH activity in muscle of insulin-resistant subjects (243).”

    From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [243]

  • During substrate opulence or a deficiency of carnitine or carnitine acetyltransferase, accumulation of acetyl-CoA in skeletal muscle allosterically inhibits PDH, resulting in impaired glucose utilization and whole-body glucose tolerance.

    “Mechanistically, during substrate opulence or a deficiency of carnitine or carnitine acetyltransferase, accumulation of acetyl-CoA in skeletal muscle allosterically inhibits PDH resulting in impaired glucose utilization and whole-body glucose tolerance (243).”

    From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [243]

  • In patients with T2DM, carnitine acetyltransferase expression is severely perturbed, and free carnitine concentrations in diabetic mice are decreased compared with controls.

    “In patients with T2DM, carnitine acetyltransferase expression is severely perturbed and free carnitine concentrations in diabetic mice are decreased compared with controls (243, 244).”

    From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [243]

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Authors
Muoio, D. M., Noland, R. C., Kovalik, J.-P., Seiler, S. E., Davies, M. N., DeBalsi, K. L., Ilkayeva, O. R., Stevens, R. D., Kheterpal, I., Zhang, J., Covington, J. D., Bajpeyi, S., Ravussin, E., Kraus, W., Koves, T. R., & Mynatt, R. L.
Affiliations
  • Duke University (US)
  • Pennington Biomedical Research Center (US)
Corresponding author
  • Muoio, Deborah M.
  • Mynatt, Randall L.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2012-05
Volume
15
Issue
5
Pages
764-777
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2012.04.005
PMC
PMC3348515
OpenAlex
W1999697076
Cited by
372
References
49
Citations by year
2026: 16 · 2025: 22 · 2024: 17 · 2023: 23 · 2022: 24 · 2021: 23 · 2020: 39 · 2019: 18 · 2018: 29 · 2017: 32 · 2016: 33 · 2015: 31 · 2014: 36 · 2013: 22 · 2012: 7
FWCI
12.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (AG028716, R01AG028930, P30AG028716)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058398, F32DK080609, P30DK072476, R01DK089312)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
carnitine acetyltransferase, CRAT, metabolic inflexibility, glucose tolerance, skeletal muscle, substrate switching, acetyl-L-carnitine, acetyl-CoA, pyruvate dehydrogenase, insulin action, carnitine supplementation, metabolic syndrome, muscle-specific knockout mice
MeSH terms
Acetyl Coenzyme A, Acetylcarnitine, Animals, Carbon, Carnitine, Carnitine O-Acetyltransferase, Cells, Cultured, Energy Metabolism, Fatty Acids, Glucose, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Mitochondria, Mice, Knockout, Muscle Fibers, Skeletal, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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