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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 accessAbstract
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.
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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.
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In the paper
“We also showed that contraction did not increase LDH release from cells into the media (Fig. 3b).”
§ 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 > Results
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In the paper
“There were no differences in BDNF mRNA levels in the exercise cohort compared with the resting cohort (Fig. 1a).”
§ 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 > Results
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In the paper
“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.”
§ 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 > BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · 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
“BDNF increased phosphorylation of AMPK and ACCβ and enhanced FAO both in vitro and ex vivo.”
§ 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 > Abstract
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In the paper
“We were unable to detect any differences in BDNF release in the media of control compared with contraction-treated cells (data not shown).”
§ 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 > Results
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In the paper
“In addition, the plasma levels of P-selectin, a marker of platelet activation, were also increased immediately following exercise (data not shown).”
§ 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 > Results
Strength:plain· not yet calibratedCausal:direct· 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
“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.”
§ 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 > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: AMPK phosphorylation of ACCβ inhibits ACC, lowers malonyl-CoA, relieves CPT1 inhibition, and increases fatty acid oxidation.
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 time-dependent effects were transient as no differences were seen in phospho-AMPK or phospho-ACCβ at 30 min (data not shown), with the effects present at only 10 min (Fig. 4a-c).”
§ 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 > BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes
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
“To confirm that this increase in BDNF expression was indeed increased within muscle fibres, we performed IHC experiments and showed that the increased BDNF production 24 h after exercise was indeed intramyocellular (Fig. 1d).”
§ 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 > Results
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The BDNF antibody used recognizes both pro- and mature forms of BDNF.
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, muscle contraction increased Bdnf mRNA levels compared with non-contracted cells (Fig. 3d).”
§ 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 > Results
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- The quote only partly states this claim. 6
- It may state two separate claims as one. 30
- Probably not a substantial claim. 13
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
“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.”
§ 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 > BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Also stated in: § BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes · 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
“we first showed that PCr, but not ATP, stores were decreased by contraction (Fig. 3a).”
§ 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 > Results
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In the paper
“Moreover, such a treatment increased both the pro-and mature BDNF protein levels immediately after the contraction protocol (Fig. 3e, f).”
§ 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 > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The BDNF antibody used recognizes both pro- and mature forms of BDNF.
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
“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).”
§ 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 > BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Also stated in: § BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes · 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
“Serum BDNF concentrations increased immediately following exercise, before returning to pre-exercise levels 60 min following the cessation of exercise (Fig. 2a).”
§ 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 > Results
Strength:plain· not yet calibratedCausal:direct· 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
“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.”
§ 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 > Abstract
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- Also stated in: § Results · plain
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In the paper
“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.”
§ 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 > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Rests on an assumption: The BDNF antibody used recognizes both pro- and mature forms of BDNF.
- Also stated in: § Abstract · hedged
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
“BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation”
§ 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 > BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearThe quote only partly states this claim.
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In the paper
“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.”
§ 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 > BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation
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In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes · plain
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In the paper
“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)”
§ 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 > BDNF increases fat oxidation in an AMPK-dependent manner in L6 myotubes
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In the paper
“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).”
§ 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 > Discussion
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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
“BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation”
§ 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 > BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
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, we were unable to detect any BDNF in the media from cells that underwent contraction, even though such an intervention increased BDNF protein production.”
§ 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 > Discussion
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In the paper
“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.”
§ 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 > Discussion
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In the paper
“Since platelets are known to store and release BDNF [35], we examined the relationship between circulating BDNF and platelet count.”
§ 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 > Results
What the sources say
- Not checked yetcites [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
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ 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 > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“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].”
§ 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 > Introduction
What the sources say
- Not checked yetcites [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
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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
“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.”
§ 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 > Results
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In the paper
“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.”
§ 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 > Introduction
What the sources say
- Not checked yetcites [25] McGee SL, Hargreaves M (2004) Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes 53:1208–1214 source
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In the paper
“It is also known that BDNF reduces food intake and lowers blood glucose in genetically modified (db/db) obese mice [15][16][17][18].”
§ 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 > Introduction
What the sources say
- Not checked yetcites [15][16][17][18]
Strength:boosted· 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. 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
“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.”
§ 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 > Results
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In the paper
“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.”
§ 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 > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“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].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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
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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
“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.”
§ 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 > Discussion
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In the paper
“since we show both in vitro and in intact muscle ex vivo that, like CNTF, BDNF activates AMPK signalling and enhances FAO.”
§ 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 > Discussion
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In the paper
“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].”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: BDNF binding to TrkB causes TrkB phosphorylation and downstream ERK phosphorylation.
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
“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.”
§ 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 > Discussion
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
“Recent studies have demonstrated that Bdnf mRNA increases in the contracting skeletal muscle of rodents [22,23]”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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
Strength:boosted· 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.
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
“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.”
§ 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 > Discussion
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
“The latter findings are supported by animal studies, which demonstrate an insulin-sensitising effect of BDNF [15][16][17].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
Strength:boosted· 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“As no differences were reported when comparing the muscles of the control with the sham group, data from sham-treated muscles are reported.”
§ 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 > Human in vivo experiments
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
“These data suggest that BDNF may act in an autocrine and/ or paracrine fashion in skeletal muscle.”
§ 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 > Discussion
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
“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].”
§ 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 > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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
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. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
Strength:boosted· 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. 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
“providing further evidence that BDNF exerts its action locally and is not released into the circulation when intramuscular production is increased.”
§ 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 > BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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]”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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
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. 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
“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.”
§ 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 > BDNF increases phosphorylation of AMPK and its downstream target ACCβ and results in enhanced fat oxidation
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [44] Ethell IM, Ethell DW (2007) Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res 85:2813–2823 source
Strength:boosted· 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. It may state two separate claims as one.
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 ).”
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
“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]
In the citing paper
“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]
In the citing paper
“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
MinorThe 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.
“Serum BDNF concentrations increased immediately following exercise, before returning to pre-exercise levels 60 min following the cessation of exercise (Fig. 2a).”
“Muscle biopsy samples were obtained from vastus lateralis before exercise, immediately after exercise, and 3, 5, 8, 24, 48 and 72 h into recovery using a percutaneous needle biopsy technique with suction.Samples were snap frozen before being analysed for BDNF mRNA and protein expression.Serum was obtained at the above mentioned time-points.”
TrkB phosphorylation sites are labelled differently
MinorThe text identifies the TrkB phosphorylation sites as Tyr 705/706, whereas the methods and Fig. 6 identify them as Tyr 706/707.
“Upon BDNF binding, TrkB is phosphorylated (Tyr 705/706 )”
“phospho-TrkB (Tyr 706/707 )”
Citations
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Items 101–200 of 713
Endocrine Crosstalk Between Muscle and Bone
Brotto, M. A. P., & Johnson, M. L. (2014) · Current Osteoporosis Reports · doi:10.1007/s11914-014-0209-0 · Cited by 120
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Extracellular Vesicles: Delivery Vehicles of Myokines
Trovato, E., Felice, V. D., & Barone, R. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00522 · Cited by 115
“Previous studies demonstrated that its mRNA and protein expression levels increase in human skeletal muscle after exercise without any release into the circulation (Matthews et al., 2009).”
BackgroundMarinus, N., Hansen, D., Feys, P., Meesen, R., Timmermans, A. A. A., & Spildooren, J. (2019) · Sports Medicine · doi:10.1007/s40279-019-01148-z · Cited by 120
Novel metabolic role for BDNF in pancreatic β-cell insulin secretion
Fulgenzi, G., Hong, Z., Tomassoni‐Ardori, F., Barella, L. F., Becker, J., Barrick, C. A., Swing, D. A., Yanpallewar, S. U., Croix, B. S., Wess, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15833-5 · Cited by 121
Muscle-to-Brain Signaling Via Myokines and Myometabolites
Rai, M., & Demontis, F. (2022) · Brain Plasticity · doi:10.3233/bpl-210133 · Cited by 126
“Besides being produced in the brain in response to exercise [82, 83], BDNF is also produced by contracting skeletal muscle [84, 85], where it regulates contractile strength of fast-twitch myofibers [86] and fat oxidation via AMPK activation [87].”
BackgroundMuscle-to-tumor crosstalk: The effect of exercise-induced myokine on cancer progression
Huang, Q., Wu, M., Wu, X., Zhang, Y., & Xia, Y. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188761 · Cited by 124
Muscle-Organ Crosstalk: Focus on Immunometabolism
Bay, M. L., & Pedersen, B. K. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.567881 · Cited by 117
Self-citationGörgens, S. W., Raschke, S., Holven, K. B., Jensen, J., Eckardt, K., & Eckel, J. (2013) · Archives of Physiology and Biochemistry · doi:10.3109/13813455.2013.768270 · Cited by 115
“Up to now, only a few myokines have been identified to be regulated by exercise such as IL-6, IL-15, leukaemia inhibitory factor and brain-derived neurotrophic factor (Broholm et al., 2011; Matthews et al., 2009; Nielsen et al., 2007; Pedersen, 2012).”
BackgroundWhitham, M., Chan, M. H. S., Pal, M., Matthews, V. B., Prelovsek, O., Lunke, S., El-Osta, A., Broenneke, H., Alber, J., Brüning, J. C., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.310581 · Cited by 107
“This protocol induces typical “exercise” responses in muscle such as AMP-activated protein kinase phosphorylation and decreases in phosphocreatine and glycogen in the absence of notable cell death (16, 17).”
BackgroundSelf-citationComparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise
Church, D. D., Hoffman, J. R., Mangine, G. T., Jajtner, A. R., Townsend, J. R., Beyer, K. S., Wang, R., Monica, M. B. L., Fukuda, D. H., & Stout, J. R. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00233.2016 · Cited by 111
“Although its role in the skeletal muscle is less clear, increased expression of skeletal muscle BDNF has been shown to increase fat oxidation in an AMP-activated protein kinase-dependent mechanism (28).”
BackgroundExerkines and long-term synaptic potentiation: Mechanisms of exercise-induced neuroplasticity
Vints, W. A. J., Levin, O., Fujiyama, H., Verbunt, J., & Masiulis, N. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.100993 · Cited by 119
“Skeletal muscle cells may synthesize (Matthews et al., 2009) and release BDNF into the circulation (Máderová et al.”
BackgroundOla, M. S., Nawaz, M. I., El‐Asrar, A. M. A., Abouammoh, M., & Alhomida, A. S. (2012) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-012-9901-8 · Cited by 106
“The specific source of serum BDNF is not known; however, BDNF is stored in circulating platelets, in muscle and heart, in addition to central and peripheral nervous system (Matthews et al. 2009; Golden et al. 2010).”
BackgroundNay, K., Smiles, W. J., Kaiser, J., McAloon, L. M., Loh, K., Galić, S., Oakhill, J. S., Gundlach, A. L., & Scott, J. W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084052 · Cited by 112
“BDNF is generated in human skeletal muscle in response to exercise, but muscle-derived BDNF is not released into the circulation [64], suggesting that the links between skeletal muscle and BDNF-induced improvements in hippocampus in response to exercise are indirect.”
BackgroundRowe, G. C., Safdar, A., & Arany, Z. P. (2014) · Circulation · doi:10.1161/circulationaha.113.001590 · Cited by 107
“Similarly, the neurotrophin brain-derived neurotrophic factor (BDNF) and the interleukin-like leukemia-inhibitory factor are induced by exercise and may promote fatty acid oxidation in muscle.(90,91)”
Jiang, H., Liu, Y., Zhang, Y., & Chen, Z.-Y. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.10.020 · Cited by 101
Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility
Yang, X., Brobst, D., Chan, W. S., Tse, M. C. L., Herlea-Pana, O., Ahuja, P., Bi, X., Zaw, A. M., Kwong, Z. S. W., Jia, W.-H., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aau1468 · Cited by 99
“Increased intramyocellular BDNF content and circulating BDNF levels after exercise have been reported in humans (13).”
BackgroundPasco, J. A., Williams, L. J., Jacka, F. N., Stupka, N., Brennan-Olsen, S. L., Holloway‐Kew, K. L., & Berk, M. (2015) · Current Osteoporosis Reports · doi:10.1007/s11914-015-0279-7 · Cited by 102
Exercise After Traumatic Brain Injury: Is it a Double‐Edged Sword?
Griesbach, G. S. (2011) · PM&R · doi:10.1016/j.pmrj.2011.02.008 · Cited by 105
Schirò, G., Iacono, S., Ragonese, P., Aridon, P., Salemi, G., & Balistreri, C. R. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.917527 · Cited by 109
“This, in fact, can behave like a protein whose synthesis is inducible by contraction by the active muscle and is aimed at inducing, among other things, lipid oxidation in the muscle (137).”
BackgroundAMPK and the Endocrine Control of Metabolism
Townsend, L. K., & Steinberg, G. R. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad012 · Cited by 114
Physiology of Mechanotransduction: How Do Muscle and Bone “Talk” to One Another?
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript on satellite cells during myogenesis [38] and brain-derived neutrophic factor (BDNF) [39].”
BackgroundInfluentialInterleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice
Lindegaard, B., Matthews, V. B., Brandt, C., Højman, P., Allen, T. L., Estévez, E., Watt, M. J., Bruce, C. R., Mortensen, O. H., Syberg, S., et al. (2013) · Diabetes · doi:10.2337/db12-1095 · Cited by 93
“In vivo electroporation experiments were performed as previously described (16).”
MethodSelf-citationMubarak, A., Hodgson, J. M., Considine, M. J., Croft, K. D., & Matthews, V. B. (2013) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf400920x · Cited by 92
Self-citationHow does the skeletal muscle communicate with the brain in health and disease?
Isaac, A. R., Lima‐Filho, R. A. S., & Lourenco, M. V. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108744 · Cited by 99
The impact of dietary energy intake on cognitive aging
Mattson, M. P. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/neuro.24.005.2010 · Cited by 91
“While the mechanism by which BDNF signaling in the brain affects peripheral glucose metabolism remains to be determined, BDNF may also exert direct actions on peripheral tissues involved in energy metabolism including muscle (Matthews et al., 2009) and pancreas (Hanyu et al., 2003).”
Exercise as a Positive Modulator of Brain Function
Alkadhi, K. A. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0516-4 · Cited by 93
“BDNF is a vital growth factor that works through activation of tropomyosin kinase B (TrkB) receptors, which are expressed in brain tissue as well as in skeletal muscle [55, 121].”
BackgroundA network map of BDNF/TRKB and BDNF/p75NTR signaling system
Sandhya, V. K., Raju, R., Verma, R., Advani, J., Sharma, R., Radhakrishnan, A., Nanjappa, V., Jayasuryan, N., Somani, B. L., Mukherjee, K. K., et al. (2013) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-013-0200-z · Cited by 88
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The Role of Exercise, Diet, and Cytokines in Preventing Obesity and Improving Adipose Tissue
ATAKAN, M. M., Koşar, Ş. N., Güzel, Y., Tin, H. T., & Yan, X. (2021) · Nutrients · doi:10.3390/nu13051459 · Cited by 96
“A study by Matthews et al. aimed to determine the signalling processes of BDNF following exercise intervention in humans, and reported that BDNF is an exercise-inducible protein that increases lipid oxidation in skeletal muscle by activating AMP-activated protein kinase (AMPK) [222], which is an important molecule in…”
BackgroundInfluentialHurtado, E., Cilleros‐Mañé, V., Nadal, L., Simó, A., Obis, T., García, N., Santafé, M. M., Tomàs, M., Halievski, K., Jordan, C. L., et al. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00147 · Cited by 90
“Moreover, BDNF is produced by contracting myotubes in vitro (Matthews et al., 2009).”
BackgroundA meta-analysis of circulating BDNF concentrations in anorexia nervosa
Brandys, M. K., Kas, M. J., Elburg, A. A. V., Campbell, I. C., & Adan, R. A. H. (2011) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2011.562244 · Cited by 85
“BDNF is expressed in many sites in the CNS (Hofer et al. 1990; Maisonpierre et al. 1990; Wang et al. 2010) and in peripheral tissues, such as skeletal muscles, adipose tissue and internal organs (Matthews et al. 2009).”
BackgroundPereira, D. S., de Queiroz, B. Z., de Miranda, A. S., Rocha, N. P., Felício, D. C., Mateo, E. C. C., Favero, M., Coelho, F. M., de Jesus‐Moraleida, F. R., Pereira, D. A. G., et al. (2013) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/j.apmr.2013.03.029 · Cited by 88
Gutiérrez‐Aguilar, R., Kim, D., Woods, S. C., & Seeley, R. J. (2011) · Obesity · doi:10.1038/oby.2011.236 · Cited by 84
“In addition, BDNF enhances fat oxidation via activation of adenosine monophosphate–activated protein kinase (64).”
BackgroundBertram, S., Brixius, K., & Brinkmann, C. K. (2016) · Endocrine · doi:10.1007/s12020-016-0976-8 · Cited by 89
Carson, B. P. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00097 · Cited by 86
Sarcopenic obesity: Myokines as potential diagnostic biomarkers and therapeutic targets?
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Endurance Exercise as an “Endogenous” Neuro-enhancement Strategy to Facilitate Motor Learning
Taubert, M., Villringer, A., & Lehmann, N. (2015) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2015.00692 · Cited by 95
“However, Matthews et al. (2009) showed that BDNF mRNA and protein are increased in skeletal muscles after exercise, but the increased BDNF seems not be released into circulation.”
BackgroundHypothalamic neurogenesis in the adult brain
Cheng, M.-F. (2013) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.05.001 · Cited by 81
Myf6/MRF4 is a myogenic niche regulator required for the maintenance of the muscle stem cell pool
Lazure, F., Blackburn, D. M., Karam, N., Sahinyan, K., Sharanek, A., Nguyen, D., Corchado, A. H., Lepper, C., Najafabadi, H. S., Perkins, T. J., et al. (2020) · EMBO Reports · doi:10.15252/embr.201949499 · Cited by 84
“…Inter-leukin-6 (IL6), Interleukin-15 (IL15), and brain-derived neurotrophic factor (BDNF) among others, have been studied in the context of their effect on inflammation, metabolic homeostasis, and lipid oxidation, respectively (Matthews et al , 2009; Munoz-Canoves et al , 2013; Quinn et al , 2013).”
The Role of the Skeletal Muscle Secretome in Mediating Endurance and Resistance Training Adaptations
Leuchtmann, A. B., Adak, V., Dilbaz, S., & Handschin, C. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.709807 · Cited by 84
Lombardi, G., Ziemann, E., & Banfi, G. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00060 · Cited by 92
“Although its indisputable role as a myokine (195), brainderived neurotrophic factor (BDNF) is mostly expressed in the brain, as is its receptor (196, 197), indeed 70–80% of the circulating protein origins from brain (9).”
BackgroundJo, D., Yoon, G., Kim, O. Y., & Song, J. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112636 · Cited by 86
Correia, P. R., Pansani, A. P., Machado, F., Andrade, M. S., da Silva, A. C., Scorza, F. A., Cavalheiro, É. A., & Arida, R. M. (2010) · Clinics · doi:10.1590/s1807-59322010001100012 · Cited by 79
“On the other hand, Matthews et al.23 showed that although BDNF is produced by the muscle, it is not transported into the circulation.”
MethodAcute and regular exercise distinctly modulate serum, plasma and skeletal muscle BDNF in the elderly
Máderová, D., Krumpolec, P., Slobodová, L., Schön, M., Tirpáková, V., Kovaničová, Z., Klepochová, R., Vajda, M., Šutovský, S., Cvečka, J., et al. (2019) · Neuropeptides · doi:10.1016/j.npep.2019.101961 · Cited by 79
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“Recent studies have shown that BDNF is also produced in nonneurogenic tissues, including skeletal muscle and vascular endothelium, and is stored in platelets (4,5).”
BackgroundWilland, M. P., Rosa, E., Michalski, B., Zhang, J. J., Gordon, T., Fahnestock, M. L., & Borschel, G. H. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.07.040 · Cited by 76
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A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved
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Muscle cell‐derived cytokines in skeletal muscle regeneration
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“001 Plasma B-type natriuretic peptide (pg/ml) 238 [117-427] 20 [13-35] <0.”
Nofuji, Y., Suwa, M., Sasaki, H., Ichimiya, A., Nishichi, R., & Kumagai, S. (2012) · Europe PMC (PubMed Central) · Cited by 72
Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation
Nakagomi, A., Okada, S., Yokoyama, M., Yoshida, Y., Shimizu, I., Miki, T., Kobayashi, Y., & Minamino, T. (2015) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2015.9 · Cited by 67
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The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review
Ribeiro, D., Petrigna, L., Pereira, F. C., Muscella, A., Bianco, A., & Tavares, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168814 · Cited by 83
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“Notably, all three subtypes of T cells in the MBC microenvironment had an activated BDNF signaling pathway, which could enhance lipid oxidation 31 .”
Mechanism and physical activities in bone-skeletal muscle crosstalk
Zhao, Z., Yan, K., Guan, Q., Guo, Q., & Zhao, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1287972 · Cited by 75
Deshmukh, A. S., Cox, J., Jensen, L. J., Meissner, F., & Mann, M. (2015) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00720 · Cited by 68
Prota, C., Gomes, C. M., Ribeiro, L. H. S., de Bessa, J., Nakano, É., Dall’Oglio, M. F., Bruschini, H., & Srougi, M. (2012) · International Journal of Impotence Research · doi:10.1038/ijir.2012.11 · Cited by 65
Myokines: a descriptive review
Barbalho, S. M., Neto, E. V. P., Goulart, R. D. Á., Bechara, M. D., Chagas, E. F. B., Audi, M., Campos, L. M. G., Guiguer, É. L., Buchaim, R. L., Buchaim, D. V., et al. (2020) · The Journal of Sports Medicine and Physical Fitness · doi:10.23736/s0022-4707.20.10884-3 · Cited by 73
The Molecular Effects of BDNF Synthesis on Skeletal Muscle: A Mini-Review
Rentería, I., García‐Suárez, P. C., Fry, A. C., Moncada‐Jiménez, J., Machado-Parra, J. P., Antunes, B. M., & Jiménez‐Maldonado, A. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.934714 · Cited by 75
“Recent evidence reported high BDNF and p-TrkB in the soleus muscle after eight weeks of moderate-intensity running exercise; these results were accompanied by a high p-AMPK and PGC-1α levels (Zhang et al., 2019).”
BackgroundResultInfluentialCannavò, A., Jun, S., Rengo, G., Marzano, F., Agrimi, J., Liccardo, D., Elia, A., Keceli, G., Altobelli, G. G., Marcucci, L., et al. (2023) · Circulation Research · doi:10.1161/circresaha.122.321583 · Cited by 65
Jemni, M., Zaman, R., Carrick, F. R., Clarke, N. D., Marina, M., Bottoms, L. M., Matharoo, J. S., Ramsbottom, R., Hoffman, N., Groves, S. J., et al. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1102526 · Cited by 83
“Furthermore, BDNF is produced within skeletal muscle during contraction, however, it appears that muscle-derived BDNF does not enter the bloodstream (Matthews et al., 2009).”
BackgroundRoth, C. L., Elfers, C., Gebhardt, U., Muller, H. L., & Reinehr, T. (2012) · Metabolism · doi:10.1016/j.metabol.2012.08.001 · Cited by 60
“Muscle-derived BDNF increases fatty acid oxidation in skeletal muscle, but is not released into the circulation [38,40].”
BackgroundJin, H. L., Chen, Y., Wang, B., Zhu, Y., Chen, L., Han, X., Ma, G., & Liu, N. (2018) · BMC Cardiovascular Disorders · doi:10.1186/s12872-018-0762-z · Cited by 62
Thyroid Hormones Crosstalk with Growth Factors: Old Facts and New Hypotheses
Candelotti, E., Vito, P. D., Ahmed, R. G., Luly, P., Davis, P. J., Pedersen, J. Z., Lin, H., & Incerpi, S. (2015) · Immunology Endocrine & Metabolic Agents - Medicinal Chemistry · doi:10.2174/187152221501150710131534 · Cited by 61
Pain Biomarkers in Fibromyalgia Syndrome: Current Understanding and Future Directions
Favretti, M., Iannuccelli, C., & Franco, M. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310443 · Cited by 71
Preventive and Therapeutic Potential of Physical Exercise in Neurodegenerative Diseases
Marques‐Aleixo, I., Beleza, J., Sampaio, A., Stevanović, J., Coxito, P. M., Gonçalves, I. O., Ascensão, A. A. M. R., & Magalhães, J. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8075 · Cited by 68
“Cathepsin B might also be involved in the motor neuron degeneration in amyotrophic lateral sclerosis (ALS), being diffusely distributed within degenerative neurons (86).”
The 2009 Stock Conference Report: Inflammation, Obesity and Metabolic Disease
Hevener, A. L., Febbraio, M. A., & the Stock Conference Working Group (2009) · Obesity Reviews · doi:10.1111/j.1467-789x.2009.00691.x · Cited by 60
“In addition to the effects of BDNF in brain, BDNF message is found to be elevated in skeletal muscle following acute exercise (54).”
BackgroundInfluentialSelf-citationNeuronal involvement in muscular atrophy
Cisterna, B. A., Cardozo, C. P., & Sáez, J. C. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00405 · Cited by 58
“, 2001), and is up-regulated in muscles as response to acute or repeated exercise (Cuppini et al., 2007; Matthews et al., 2009), but its possible effects on myofibers are unknown.”
BackgroundRole of BDNF/TrkB pathway in the visual system: therapeutic implications for glaucoma
Mysona, B. A., Zhao, J., & Bollinger, K. E. (2016) · Expert Review of Ophthalmology · doi:10.1080/17469899.2017.1259566 · Cited by 57
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The role of neurotrophins in bipolar disorder
Scola, G., & Andreazza, A. C. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.08.013 · Cited by 62
“In addition, BDNF is also found in peripheral tissues including skeletal muscle (Matthews et al., 2009), the liver (Cassiman et al.”
Domínguez‐Sánchez, M. A., Bustos, R., Velasco-Orjuela, G. P., Quintero, A. P., Tordecilla‐Sanders, A., Correa‐Bautista, J. E., Triana-Reina, H. R., García‐Hermoso, A., González‐Ruíz, K., Peña-Guzmán, C. A., et al. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00741 · Cited by 61
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Julian, V., Thivel, D., Costes, F., Touron, J., Boirie, Y., Pereira, B., Perrault, H., Duclos, M., & Richard, R. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01013 · Cited by 62
Myokines: Metabolic regulation in obesity and type 2 diabetes
Chen, Z.-T., Weng, Z.-X., Lin, J. D., & Meng, Z.-X. (2024) · Life Metabolism · doi:10.1093/lifemeta/loae006 · Cited by 58
“Skeletal muscle [186] Adipose tissue [330] Liver [331] Neuronal cells [332]”
Papathanassoglou, E. D. E., Miltiadous, P., & Karanikola, M. N. K. (2014) · Biological Research For Nursing · doi:10.1177/1099800414555411 · Cited by 55
“BDNF expression increases in response to muscle contraction; however, muscle-derived BDNF appears not to be released into circulation (Matthews et al., 2009).”
Campos, C., Rocha, N., Lattari, E., Paes, F., Nardi, A. E., & Machado, S. E. D. C. (2016) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2016.1179582 · Cited by 60
“BDNF is mainly produced in the brain, but it can also be produced by tissues in the periphery, mostly being released into circulation and stored in platelets [171] or produced by muscle cells where it is used locally [172].”
BackgroundGenzer, Y., Dadon‐Freiberg, M., Burg, C., Chapnik, N., & Froy, O. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.04.015 · Cited by 54
“In skeletal muscle, overproduction of BDNF increases fat oxidation in an AMPK-dependent manner, which, in turn, leads to the phosphorylation and inactivation of acetyl CoA carboxylase (ACC) (Matthews et al., 2009), the rate limiting enzyme in fatty acid synthesis.”
BackgroundSandroff, B. M., Motl, R. W., Reed, W. R., Barbey, A. K., Benedict, R. H. B., & DeLuca, J. (2018) · Neurorehabilitation and neural repair · doi:10.1177/1545968318798938 · Cited by 58
“In comparison, it is unlikely that exercise-related changes in the upregulation of neurotrophic and vascular trophic factors are dependent on changes in brain connectivity.(70) As such, the systematic examination of molecular/cellular mechanisms is not a primary component of the current framework because exercise-rela…”
BackgroundSimão, A. P., Mendonça, V. A., de Avelar, N. C. P., da Fonseca, S. F., dos Santos, J. M., Coelho-Oliveira, A. C., Tossige-Gomes, R., Ribeiro, V. G. C., Neves, C. D. C., Balthazar, C. H., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00756 · Cited by 54
Influence of citalopram and environmental temperature on exercise-induced changes in BDNF
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The role of myokines in cancer: crosstalk between skeletal muscle and tumor
Park, S.-Y., Hwang, B.-O., & Song, N. (2023) · BMB Reports · doi:10.5483/bmbrep.2023-0064 · Cited by 52
Suire, C. N., Eitan, E., Shaffer, N. C., Tian, Q., Studenski, S. A., Mattson, M. P., & Kapogiannis, D. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.08.024 · Cited by 55
“Experiments in both rodents and humans have found that exercise increases BDNF levels, and can reverse the effects of a high-fat diet through BDNF signaling (Griffin et al., 2011; Hopkins et al., 2011; Lee et al., 2002; Molteni et al., 2004; Winter et al., 2007).”
Murawska‐Ciałowicz, E., de Assis, G. G., Clemente, F. M., Feito, Y., Šťastný, P., Zuwała−Jagiełło, J., Bibrowicz, B., & Wolański, P. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-88069-y · Cited by 59
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High-Intensity Aerobic Exercise Acutely Increases Brain-derived Neurotrophic Factor
ROSS, R. E., SALADIN, M. E., GEORGE, M. S., & GREGORY, C. M. (2019) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000001969 · Cited by 50
Ryu, J. Y., Choi, H. M., Yang, H.-I., & Kim, K. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186887 · Cited by 52
“An in vivo and an ex vivo study indicated that BDNF increased the phosphorylation of AMPK [47].”
BackgroundDynamic Expression and the Role of BDNF in Exercise-induced Skeletal Muscle Regeneration
Yu, T., Chang, Y., Gao, X., Li, H., & Zhao, P. (2017) · International Journal of Sports Medicine · doi:10.1055/s-0043-118343 · Cited by 50
“Previous studies have tested BDNF expression in skeletal muscle for three days post exercise [10, 23].”
BackgroundMethodInfluentialLi, J., Wang, Z., Li, C., Song, Y., Wang, Y., Hai, B., & Zhang, Y. (2022) · Cells · doi:10.3390/cells11132086 · Cited by 56
Myokine-mediated muscle-organ interactions: Molecular mechanisms and clinical significance
Yi, J., Chen, J., Yao, X., Zhao, Z., Niu, X., Li, X., Sun, J., Ji, Y., Shang, T., Gong, L., et al. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117326 · Cited by 68
The role of exercise-induced peripheral factors in sleep regulation
Tan, X. W., van Egmond, L. T., Cedernaes, J., & Benedict, C. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101096 · Cited by 52
“Although exercise acutely results in elevated gene expression of BDNF in human skeletal muscle [40], suggesting that myocytes may drive the exercise-induced increase of plasma BDNF, this tissue is not the sole source of BDNF.”
BackgroundDao, A. T., Zagaar, M. A., & Alkadhi, K. A. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8916-1 · Cited by 49
“Clearly, there is ample evidence for the positive effect of exercise in a variety of brain disorders; however, an important question remains unclear: How does muscle activity translate into a beneficial effect on the brain? Although a significant amount of BDNF is produced in skeletal muscles at rest and particularly…”
Background
Metadata
- 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.
- Venue
- Diabetologia
- Published
- 2009-04-22
- Volume
- 52
- Issue
- 7
- Pages
- 1409-1418
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- 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
- bronze
- doi.org
- 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 (medical) › 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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