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Cited by 722Muscle Physiology and DisordersMetabolism, Diabetes, and CancerAdipose Tissue and Metabolism

Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

Open access
Matthews, V. B., Åström, M.-B., Chan, M. H. S., Bruce, C. R., Krabbe, K. S., Prelovsek, O., Åkerström, T., Yfanti, C. +9 more·2009·Diabetologia
DOI 10.1007/s00125-009-1364-1
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Abstract

Aims/hypothesis Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF.Methods We first examined whether exercise induced BDNF expression in humans. Next, C2C12 skeletal muscle cells were electrically stimulated to mimic contraction. L6 myotubes and isolated rat extensor digitorum longus muscles were treated with BDNF and phosphorylation of the proteins AMP-activated protein kinase (AMPK) (Thr(172)) and acetyl coenzyme A carboxylase beta (ACCbeta) (Ser(79)) were analysed, as was fatty acid oxidation (FAO). Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice.Results BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation. Bdnf mRNA and protein expression was increased in muscle cells that were electrically stimulated. BDNF increased phosphorylation of AMPK and ACCbeta and enhanced FAO both in vitro and ex vivo. The effect of BDNF on FAO was AMPK-dependent, since the increase in FAO was abrogated in cells infected with an AMPK dominant negative adenovirus or treated with Compound C, an inhibitor of AMPK. Electroporation of a Bdnf expression vector into the tibialis cranialis muscle resulted in increased BDNF protein production and tropomyosin-related kinase B (TrkB(Tyr706/707)) and extracellular signal-regulated protein kinase (p44/42 Thr(202)/Tyr(204)) phosphorylation in these muscles. In addition, phosphorylation of ACCbeta was markedly elevated in the Bdnf electroporated muscles.Conclusions/interpretation These data identify BDNF as a contraction-inducible protein in skeletal muscle that is capable of enhancing lipid oxidation in skeletal muscle via activation of AMPK.

AI snapshot

Written from the paper’s full text.

TL;DR

BDNF is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via AMPK activation in vitro and ex vivo, but muscle-derived BDNF is not released into the circulation and likely acts locally. Human exercise increased muscle BDNF protein about 50% at 24 h recovery, while serum BDNF rose immediately after exercise and tracked platelet counts.

Key findings

  • In eight healthy men, 120 min of bicycle exercise at 60% V̇O₂max increased skeletal muscle BDNF protein about 50% at 24 h recovery (p<0.05); BDNF mRNA showed marked inter-individual variation, with an AUC difference between exercise and resting groups (p<0.05).
  • Serum BDNF increased immediately after exercise and returned to pre-exercise levels by 60 min; platelet counts followed a closely matching pattern, suggesting the early circulating BDNF increase may at least partly reflect release from activated platelets rather than muscle.
  • Electrically stimulated C2C12 myotubes increased Bdnf mRNA and pro- and mature BDNF protein, with no detectable BDNF release into media.
  • BDNF increased phosphorylation of AMPK (Thr172) and ACCβ (Ser79) and enhanced palmitate oxidation in L6 myotubes and rat extensor digitorum longus muscle ex vivo; the FAO increase was AMPK-dependent, as it was abrogated by Compound C or an AMPK dominant negative adenovirus. BDNF did not increase glucose uptake (fold change from vehicle: vehicle=1±0.04; insulin 100 nmol/l=2.32±0.072; BDNF 10 ng/ml=0.94±0.071; insulin+BDNF=1.99±0.185).

Methods

  • Human in vivo: 8 healthy, physically active but untrained men (mean±SD age 25±4 years, weight 82±8 kg, height 181±1 cm, BMI 25±2 kg/m²) performed 120 min bicycle exercise at 60% V̇O₂max; vastus lateralis biopsies and serum were collected before, immediately after, and at 3, 5, 8, 24, 48, and 72 h recovery.
  • Cell culture: differentiated C2C12 myotubes were electrically stimulated for 120 min (18 V; 1 Hz; 24 ms); L6 myotubes were treated with recombinant human BDNF at 1, 10, and 100 ng/ml for 10 and 30 min, with palmitate oxidation and glucose uptake measured, and AMPK inhibition via 40 µmol/l Compound C or dominant negative AMPK adenovirus.
  • Ex vivo and in vivo: rat extensor digitorum longus strips were treated with BDNF for palmitate oxidation and AMPK/ACCβ phosphorylation; 8- to 10-week-old C57BL6/C mice underwent intramuscular electroporation of a Bdnf vector into tibialis cranialis with doxycycline induction, with n=3 mice per group. Statistics included two-way ANOVA for repeated measures, unpaired t test for AUCs, and paired t tests for cell culture experiments from three independent experiments.

Limitations

  • Stated: the contraction-induced increase in BDNF both in vivo and in vitro was relatively modest, whereas electroporation increased BDNF several fold, so whether BDNF plays an important role in vivo is unclear.
  • Stated: whether the ACCβ phosphorylation effect after BDNF overproduction is due to paracrine/autocrine signaling or a direct intracellular signaling event requires further clarification.
  • Stated: BDNF plays no role in mediating contraction-induced increases in fat oxidation, because fat oxidation increases at the onset of contraction while muscle BDNF increases well into recovery. Evident: the human exercise cohort was small (n=8), and the paper reports no direct measurement of autocrine/paracrine BDNF action within muscle.

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

Integrity signals

Registry

Crossref · 10.1007/s00125-009-1364-1

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 24 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Electrical stimulation of C2C12 myotubes does not increase LDH release into the media.

    “We also showed that contraction did not increase LDH release from cells into the media (Fig. 3b).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the human exercise cohort, BDNF mRNA levels at individual post-exercise time points do not differ from the resting cohort.

    “There were no differences in BDNF mRNA levels in the exercise cohort compared with the resting cohort (Fig. 1a).”
    Quote in the paperNot a substantial claim
  • Findingown data

    BDNF enhances fatty acid oxidation in L6 myotubes.

    “Irrespective of whether cells were treated with PBS (Fig. 4d) or infected with a control virus (AdGO) (Fig. 4e) treatment of cells with BDNF enhanced fat oxidation.”
    • Also stated in: § Abstract · plain
      “BDNF increased phosphorylation of AMPK and ACCβ and enhanced FAO both in vitro and ex vivo.”
    Quote in the paperSubstantial claim
  • Findingown data

    BDNF enhances fatty acid oxidation in isolated rat extensor digitorum longus muscle ex vivo.

    “BDNF increased phosphorylation of AMPK and ACCβ and enhanced FAO both in vitro and ex vivo.”
    Quote in the paperSubstantial claim
  • Findingown data

    BDNF release into the media is not different between control and contraction-treated C2C12 cells.

    “We were unable to detect any differences in BDNF release in the media of control compared with contraction-treated cells (data not shown).”
    Quote in the paperNot a substantial claim
  • The quote only partly states this claim. 6
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 13

  • The quote only partly states this claim.

    Findingown data

    In L6 myotubes, BDNF at 100 ng/ml increases AMPK phosphorylation at 10 min.

    “We showed that at the two higher doses, BDNF markedly phosphorylated ACCβ, while a similar effect was seen for phospho-AMPK at the higher dose.”
    • Also stated in: § BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes · plain
      “The lack of effect of phospho-AMPK at 10 ng/ml was unexpected since phospho-ACCβ was increased.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In electrically stimulated C2C12 myotubes, phosphocreatine stores decrease while ATP stores do not.

    “we first showed that PCr, but not ATP, stores were decreased by contraction (Fig. 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Contraction increases both pro- and mature BDNF protein levels in C2C12 myotubes immediately after the stimulation protocol.

    “Moreover, such a treatment increased both the pro-and mature BDNF protein levels immediately after the contraction protocol (Fig. 3e, f).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The BDNF antibody used recognizes both pro- and mature forms of BDNF.

  • The quote only partly states this claim.

    Findingown data

    In L6 myotubes, BDNF at 10 and 100 ng/ml increases ACCβ phosphorylation at 10 min.

    “We showed that at the two higher doses, BDNF markedly phosphorylated ACCβ, while a similar effect was seen for phospho-AMPK at the higher dose.”
    • Also stated in: § BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes · plain
      “with the effects present at only 10 min (Fig. 4a-c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Serum BDNF concentration rises immediately after exercise and returns to pre-exercise levels 60 min after exercise cessation.

    “Serum BDNF concentrations increased immediately following exercise, before returning to pre-exercise levels 60 min following the cessation of exercise (Fig. 2a).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In healthy men, 120 min of bicycle exercise at 60% of VO2max increases BDNF mRNA in skeletal muscle when the post-exercise time course is summarized as AUC (p<0.05).

    “BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation.”
    • Also stated in: § Results · plain
      “As such, we calculated the AUC over time for both groups and showed a difference (p<0.05) for the AUC when comparing the two groups.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In healthy men, 120 min of bicycle exercise increases BDNF protein in skeletal muscle at 24 h of recovery by about 50% (p<0.05).

    “At 24 h into recovery from exercise, BDNF protein levels were increased (about 50%; p<0.05) in the muscle homogenates (Fig. 1b, c).”
    • Also stated in: § Abstract · hedged
      “BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The BDNF antibody used recognizes both pro- and mature forms of BDNF.

  • The quote only partly states this claim.

    Findingown data

    In L6 myotubes, BDNF increased phosphorylation of ACCβ.

    “BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both BDNF and AICAR increased 14C in the CO2 fraction but not in the acid soluble metabolite fraction, indicating complete oxidation of the label.

    “It should also be noted that while both BDNF and the positive control 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) increased 14 C in the CO 2 fraction, this was not seen in the acid soluble metabolite fraction, indicating complete oxidation of the label.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    C2C12 murine muscle cells produce BDNF, and contraction increases this production.

    “By conducting muscle cell culture experiments, we show that C2C12 murine cells not only produce BDNF, but that this production can be increased by contraction.”
    • Also stated in: § BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes · plain
      “Bdnf mRNA and protein expression is increased in contracting muscle cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The BDNF-induced increase in fat oxidation in L6 myotubes was completely abolished by treatment with AMPK inhibitor Compound C or by infection with an AMPK dominant negative adenovirus.

    “However, when cells were treated with the AMPK inhibitor Compound C or infected with an AMPK dominant negative adenovirus, the BDNF-induced increase in fat oxidation was completely abrogated (Fig. 4d, e)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The contraction-induced increase in BDNF both in vivo and in vitro was relatively modest, whereas BDNF was increased several fold with electroporation.

    “It must be acknowledged, however, that the contraction-induced increase in BDNF both in vivo (Fig. 1) and in vitro (Fig. 3) was relatively modest, whereas we increased BDNF several fold with electroporation (Fig. 6).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In L6 myotubes, BDNF increased phosphorylation of AMPK.

    “BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No BDNF was detected in the media from cells that underwent contraction, even though contraction increased BDNF protein production.

    “In addition, we were unable to detect any BDNF in the media from cells that underwent contraction, even though such an intervention increased BDNF protein production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Circulating BDNF levels increased immediately after exercise and did not correlate with elevated muscle-derived BDNF 24 h after exercise.

    “We showed that circulating levels of BDNF increased immediately after exercise and did not correlate with the elevated muscle-derived BDNF 24 h after exercise.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Platelets store and release BDNF.

    “Since platelets are known to store and release BDNF [35], we examined the relationship between circulating BDNF and platelet count.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Fujimura H, Altar CA, Chen R et al (2002) Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 87:728–734 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Physical exercise can increase circulating BDNF levels in healthy humans and in patients with multiple sclerosis.

    “Recent studies have demonstrated that physical exercise can increase circulating BDNF levels in both healthy humans [19,20] and patients with multiple sclerosis [21], although the cellular origin of this increase is unclear.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Ferris LT, Williams JS, Shen CL (2007) The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc 39:728–734 source

      Not checked in the free run.

    • cites [20] Rojas Vega S, Strüder HK, Vera Wahrmann B, Schmidt A, Bloch W, Hollmann W (2006) Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res 1121:59–65 source

      Not checked in the free run.

    • cites [21] Gold SM, Schulz KH, Hartmann S et al (2003) Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. J Neuroimmunol 138:99–105 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Bdnf mRNA is expressed in murine skeletal muscle and is increased by inhibition of histone deacetylases.

    “However, in a recent study, Bdnf mRNA was shown to be expressed in murine skeletal muscle and was increased by inhibition of histone deacetylases [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Avila AM, Burnett BG, Taye AA et al (2007) Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin Invest 117:659–671 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The time course of serum BDNF after exercise does not correlate with the rise in muscle BDNF at 24 h, suggesting skeletal muscle is not the source of the early post-exercise serum BDNF.

    “The kinetics of the exercise-induced elevation in serum BDNF levels failed to correlate with the increased production of BDNF in muscle 24 h after exercise, suggesting that the skeletal muscle is not a source of the increase in serum BDNF observed early into recovery from exercise.”
    • Also stated in: § Abstract · hedged
      “but muscle-derived BDNF appeared not to be released into the circulation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Exercise can inhibit histone deacetylases.

    “Since exercise can inhibit histone deacetylases [25], the possibility exists that the increase in circulating BDNF in humans during exercise may originate in the contracting muscle cells and that BDNF may be a novel contraction-induced myokine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] McGee SL, Hargreaves M (2004) Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes 53:1208–1214 source

      Not checked in the free run.

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

    Premisecitation

    BDNF reduces food intake and lowers blood glucose in genetically modified obese db/db mice.

    “It is also known that BDNF reduces food intake and lowers blood glucose in genetically modified (db/db) obese mice [15][16][17][18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15][16][17][18]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Exercise increases circulating BDNF, and this increase may at least partly reflect release from activated platelets.

    “Taken together, these results demonstrate that physical exercise increases circulating BDNF and that the increase may at least to some extent reflect in vivo release of BDNF from activated platelets.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    IL-6 production is upregulated by muscle contraction and IL-6 may be released from contracting skeletal muscle.

    “it is now clear that IL-6 [7] and IL-8 [8] production is upregulated by muscle contraction and that these cytokines may be released from contracting skeletal muscle.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Febbraio MA, Pedersen BK (2002) Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J 16:1335–1347 source

      Not checked in the free run.

    • cites [8] Pedersen BK, Steensberg A, Fischer C et al (2003) Searching for the exercise factor—is IL-6 a candidate. J Muscle Res Cell Motil 24:113–119 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low plasma BDNF is associated with type 2 diabetes, obesity, and insulin resistance.

    “Recently, we demonstrated a strong association between low plasma BDNF and type 2 diabetes on the one hand and both obesity and insulin resistance on the other [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Krabbe KS, Nielsen AR, Krogh-Madsen R et al (2007) Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 50:431–438 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BDNF may contribute to the health benefits of exercise, possibly by enhancing fat oxidation in skeletal muscle.

    “Hence, we have identified BDNF as being a novel contraction-induced protein that may contribute to the multiple health benefits associated with exercise, possibly by enhancing fat oxidation in skeletal muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    BDNF activates AMPK signalling and enhances FAO in vitro and in intact muscle ex vivo.

    “since we show both in vitro and in intact muscle ex vivo that, like CNTF, BDNF activates AMPK signalling and enhances FAO.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Overproduction of BDNF resulted in marked ERK and TrkB phosphorylation, which indicates signalling through TrkB.

    “This hypothesis is plausible since overproduction of BDNF resulted in marked ERK (Fig. 6c) and TrkB (Fig. 6d, e) phosphorylation, which is indicative of signalling through TrkB, which is produced in skeletal muscle and myotubes [43].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BDNF binding to TrkB causes TrkB phosphorylation and downstream ERK phosphorylation.

  • May combine two claims.

    Interpretationown data

    BDNF is a protein produced by skeletal muscle cells, increased by contraction, that enhances fat oxidation in an AMPK-dependent fashion, most probably acting in an autocrine and/or paracrine manner within skeletal muscle.

    “Taken together, our data demonstrate that BDNF is a protein produced in skeletal muscle cells that is increased by contraction to enhance fat oxidation in an AMPKdependent fashion, most probably by acting in an autocrine and/or paracrine manner within skeletal muscle.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Bdnf mRNA increases in contracting skeletal muscle of rodents.

    “Recent studies have demonstrated that Bdnf mRNA increases in the contracting skeletal muscle of rodents [22,23]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Dupont-Versteegden EE, Houlé JD, Dennis RA et al (2004) Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats. Muscle Nerve 29:73–81 source

      Not checked in the free run.

    • cites [23] Gómez-Pinilla F, Ying Z, Opazo P, Roy RR, Edgerton VR (2001) Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci 13:1078–1084 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BDNF is a novel contraction-induced muscle cell-derived protein that can increase fat oxidation in skeletal muscle in an AMPK-dependent fashion.

    “In summary, we have identified BDNF as being a novel contraction-induced muscle cell-derived protein that can increase fat oxidation in skeletal muscle in an AMPKdependent fashion.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Animal studies demonstrate an insulin-sensitising effect of BDNF.

    “The latter findings are supported by animal studies, which demonstrate an insulin-sensitising effect of BDNF [15][16][17].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Ono M, Ichihara J, Nonomura T et al (1997) Brain-derived neurotrophic factor reduces blood glucose level in obese diabetic mice but not in normal mice. Biochem Biophys Res Commun 238:633–637 source

      Not checked in the free run.

    • cites [16] Tonra JR, Ono M, Liu X et al (1999) Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-leprdb/leprdb mice. Diabetes 48:588–594 source

      Not checked in the free run.

    • cites [17] Nakagawa T, Tsuchida A, Itakura Y et al (2000) Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice. Diabetes 49:436–444 source

      Not checked in the free run.

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

    Study design and conductown data

    No differences were observed between control and sham electroporated muscles, so sham data are reported.

    “As no differences were reported when comparing the muscles of the control with the sham group, data from sham-treated muscles are reported.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    BDNF may act in an autocrine and/or paracrine fashion in skeletal muscle.

    “These data suggest that BDNF may act in an autocrine and/ or paracrine fashion in skeletal muscle.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Muscle-derived IL-6 contributes markedly to systemic levels and acts in a hormone-like manner in lipid and glucose metabolism, principally via AMPK activation.

    “Muscle-derived IL-6, but not IL-8, contributes markedly to systemic levels, where it works in a hormone-like fashion and plays an important role in lipid and glucose metabolism [9,10], principally via activation of AMP-activated protein kinase (AMPK) [10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK (2004) Interleukin-6 is a novel factor mediating glucose homeostasis in skeletal muscle contraction. Diabetes 53:1643–1648 source

      Not checked in the free run.

    • cites [10] Carey AL, Steinberg GR, Macaulay SL et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55:2688–2697 source

      Not checked in the free run.

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

    Premisecitation

    CNTF can increase insulin sensitivity and decrease obesity by acting on both central and peripheral tissues.

    “we have recently demonstrated that a different neurotrophin, namely ciliary neurotrophic factor (CNTF) can increase insulin sensitivity and decrease obesity by acting on both central [38] and peripheral [39,40] tissues.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Steinberg GR, Watt MJ, Fam BC et al (2006) Ciliary neurotrophic factor suppresses hypothalamic AMPK signaling in leptin resistant obese mice. Endocrinology 147:3906–3914 source

      Not checked in the free run.

    • cites [39] Watt MJ, Dzamko N, Thomas W et al (2006) CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12:541–548 source

      Not checked in the free run.

    • cites [40] Watt MJ, Hevener A, Lancaster GI, Febbraio MA (2006) Ciliary neurotrophic factor prevents acute lipid-induced insulin resistance by attenuating ceramide accumulation and phosphorylation of JNK in peripheral tissues. Endocrinology 147:2077–2085 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    BDNF exerts its action locally and is not released into the circulation when intramuscular production is increased.

    “providing further evidence that BDNF exerts its action locally and is not released into the circulation when intramuscular production is increased.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Bdnf mRNA is expressed in murine skeletal muscle homogenates and is increased by inhibition of histone deacetylases.

    “in a recent study, the mRNA of Bdnf was shown to be expressed in murine skeletal muscle homogenates and that this was increased by inhibition of histone deacetylases [24]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Avila AM, Burnett BG, Taye AA et al (2007) Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin Invest 117:659–671 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Results from human exercise studies and cell culture experiments suggested that BDNF was produced by muscle cells during contraction but was not released into circulation or media.

    “Results from our human exercise studies and cell culture experiments suggested that BDNF was produced by muscle cells during contraction, but was not released into the circulation or media.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Pro-BDNF can be processed into mature BDNF by several matrix metalloproteinases and thereby regulate activation of TrkB either by autophosphorylation or via interaction with a neighbouring cell.

    “It is well known that pro-BDNF can be processed into mature BDNF by several matrix metalloproteinases and thereby regulate activation of TrkB either by autophosphorylation or via an interaction with a neighbouring cell [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Ethell IM, Ethell DW (2007) Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res 85:2813–2823 source

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    AMPK phosphorylation of ACCβ inhibits ACC, lowers malonyl-CoA, relieves CPT1 inhibition, and increases fatty acid oxidation.

    “AMPK phosphorylates ACCβ resulting in inhibition of ACC activity, which in turn leads to a decrease in malonyl-CoA content, relieving inhibition of carnitine palmitoyl transferase 1 and increasing fatty acid oxidation (FAO).”

  • The paper relies on this without support.

    The BDNF antibody used recognizes both pro- and mature forms of BDNF.

    “The antibody against BDNF protein recognises both the pro-and mature forms of BDNF.”

  • The paper relies on this without support.

    During exercise in humans, fat oxidation increases at the onset of contraction.

    “It should be noted that during exercise in humans, fat oxidation is increased at the onset of contraction while the increase in BDNF in skeletal muscle does not occur until well into recovery.”

  • The paper relies on this without support.

    During exercise in humans, the increase in BDNF in skeletal muscle does not occur until well into recovery.

    “It should be noted that during exercise in humans, fat oxidation is increased at the onset of contraction while the increase in BDNF in skeletal muscle does not occur until well into recovery.”

  • The paper relies on this without support.

    BDNF binding to TrkB causes TrkB phosphorylation and downstream ERK phosphorylation.

    “Upon BDNF binding, TrkB is phosphorylated (Tyr 705/706 ) resulting in a signalling cascade that includes phosphorylation of ERK (Thr 202 /Tyr 204 ).”
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?

  • BDNF mRNA and protein expression increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation.

    “BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation (332).”

    From Lack of Exercise Is a Major Cause of Chronic Diseases (2012) · cites this paper as [332]

  • BDNF is a myokine capable of enhancing AMPK activation and hence lipid oxidation in an autocrine or paracrine manner.

    “In contrast, BDNF is identified as a myokine capable of enhancing AMPK activation and hence lipid oxidation in an autocrine or paracrine manner (63).”

    From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [63]

  • BDNF is expressed in human skeletal muscles but is not released into the circulation and does not work in an endocrine way.

    “Brain-derived neurotrophic factor (BDNF) is also expressed in human skeletal muscles, but BDNF is not released into the circulation and does not work in an endocrine way.”

    From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [63]

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.

  • Reported 60-minute serum result has no listed sampling time

    Minor

    The methods state that serum was collected at the listed biopsy time-points, which do not include 60 minutes after exercise, yet the results report a serum BDNF value at that time.

  • TrkB phosphorylation sites are labelled differently

    Minor

    The text identifies the TrkB phosphorylation sites as Tyr 705/706, whereas the methods and Fig. 6 identify them as Tyr 706/707.

2 of 2

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Authors
Matthews, V. B., Åström, M.-B., Chan, M. H. S., Bruce, C. R., Krabbe, K. S., Prelovsek, O., Åkerström, T., Yfanti, C., Broholm, C., Mortensen, O. H., Penkowa, M., Hojman, P., Zankari, A., Watt, M. J., Bruunsgaard, H., Pedersen, B. K., & Febbraio, M. A.
Affiliations
  • Baker Heart and Diabetes Institute (AU)
  • University of Copenhagen (DK)
  • Monash University (AU)
Corresponding author
  • Pedersen, B. K.
  • Febbraio, M. A.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2009-04-22
Volume
52
Issue
7
Pages
1409-1418
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-009-1364-1
OpenAlex
W2083119172
Semantic Scholar
4a8929d0be521f621ff5750ab854a4eab70f134f
Cited by
722
References
45
Citations by year
2026: 33 · 2025: 56 · 2024: 57 · 2023: 48 · 2022: 67 · 2021: 54 · 2020: 54 · 2019: 54 · 2018: 44 · 2017: 45 · 2016: 29 · 2015: 45 · 2014: 29 · 2013: 38 · 2012: 22
FWCI
8.98
Type
journal article
Language
en
Update notices
correction (2015-02-19)
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
  • RMIT Research Repository (RMIT University Library) (submittedVersion)
  • Own your potential (DEAKIN) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Diabetes Australia Research Trust
  • Diabetes Australia
  • National Research Foundation
  • Danmarks Grundforskningsfond (02-512-555, DG 02–512‐555, LSHM-CT-2004-005272, 504–14, LSHM-CT-2004-005272 EXGENESIS)
  • Lundbeckfonden
  • Novo Nordisk
  • Novo Nordisk Fonden
  • H. Lundbeck A/S
  • Medical Research Council
  • Australian Research Council
  • National Health and Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
brain-derived neurotrophic factor, skeletal muscle, muscle contraction, fatty acid oxidation, AMPK, physical activity, TrkB, ERK, muscle lipid metabolism
MeSH terms
Acetyl-CoA Carboxylase, Animals, Cell Line, Exercise Test, Fats, Humans, Male, Mice, Inbred C57BL, Muscle Contraction, Oxidation-Reduction, Phosphorylation, Signal Transduction, Gene Expression, Muscle, Skeletal, Muscle Fibers, Skeletal, Brain-Derived Neurotrophic Factor, Receptor, trkB, Extracellular Signal-Regulated MAP Kinases, Lipid Metabolism, Mice, Rats, AMP-Activated Protein Kinases

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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.

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