Neuroscience Letters 560 (2014) 137–141

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Effect of fat free mass on serum and plasma BDNF concentrations

during exercise and recovery in healthy young men
M. Gilder a , R. Ramsbottom b,∗ , J. Currie b , B. Sheridan b , A.M. Nevill c
a
Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom
b
Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, United Kingdom
c
School of Sport, Performing Arts and Leisure, University of Wolverhampton, WS1 3BD, United Kingdom

h i g h l i g h t s

• Plasma vs. serum BDNF shows a greater relative increase due to exercise.
• Plasma vs. serum BDNF is slower to return to baseline values post-exercise.
• Individuals with high lean body mass show greater serum BDNF release during exercise.
• Individuals with high lean body mass show faster recovery of serum BDNF.
• Training status influences BDNF release and recovery.

a r t i c l e i n f o a b s t r a c t

Article history: Exercise results in release of brain derived neurotrophic factor into the circulation; however, little is
Received 23 August 2013 known about the changes in serum and plasma brain derived neurotrophic factor concentrations and
Received in revised form 3 December 2013 factors influencing brain derived neurotrophic factor during exercise and recovery. Serum (n = 23) and
Accepted 12 December 2013
plasma (n = 10) brain derived neurotrophic factor concentrations were measured in healthy young men at
rest, during steady-rate and after exercise to determine the maximum aerobic power. A two-way analysis
Keywords:
of variance was used to investigate brain derived neurotrophic factor levels in blood during exercise and
Exercise
recovery, with one between-subject factor (a median split on: age, height, body mass, fat free mass, body
Serum
Plasma
mass index and aerobic fitness), and one within-subject factor (time). Serum brain derived neurotrophic
BDNF factor concentrations increased in response to exercise and declined rapidly in recovery. Plasma brain
derived neurotrophic factor had a greater proportional increase relative to exhaustive exercise compared
with serum brain derived neurotrophic factor and was slower to return to near baseline values. There
was a significant group-by-time interaction indicating a greater release and faster recovery for serum
brain derived neurotrophic factor in high- compared with low-fat free mass individuals.
© 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction [7,21,25] and serum [21] in Alzheimer’s disease [22,26]. Further-

Brain derived neurotrophic factor (BDNF) is known to promote
neuronal survival, development and plasticity in the mammalian
brain and is proposed to be a key mediator of the beneficial effects
of exercise on brain health via activation of the Trk B receptor [8].
A recent study [33] also demonstrated involvement of Trk B recep-
tors in re-innervation experiments in rodents after nerve crush,
modulated by the degree of motor activity (exercise). BDNF has
a neuroprotective effect in primate models of neurological dis-
ease [25] and low concentrations of BDNF are found both in brain
∗ Corresponding author. Tel.: +44 01865483265.
E-mail address: rramsbottom@brookes.ac.uk (R. Ramsbottom).
more, serum levels of BDNF are also abnormally low in major
depression [15].
BDNF is produced by a range of non-neural tissues [3,9,10,23]
which could potentially release it into the blood, however, the
CNS appears to be the major contributor to circulating BDNF in
humans at rest and following exercise, providing approximately
70% of the increase in plasma BDNF [20,30,31]. Skeletal muscle also
up-regulates BDNF following exercise in both humans and rodents,
however, it has been shown by Matthews et al. [24] that the major-
ity of BDNF produced by skeletal muscle is not released into the
blood but is primarily utilised by skeletal muscle cells to increase
fat oxidation via the AMPK pathway. BDNF appears to be able to
cross the blood–brain barrier in a bi-directional manner [29] but
the contribution of peripheral tissues to the total circulating protein

0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neulet.2013.12.034
138 M. Gilder et al. / Neuroscience Letters 560 (2014) 137–141

Table 1 post absorptive having undertaken no exercise in the preceding

Physical characteristics of participants (n = 23).
24 h. Levels of habitual physical activity were assessed by ques-
Measure Mean SD Minimum Maximum tionnaire [3] and volunteers reported participation in a range of
Age (years) 28.2 4.8 18 36 activities e.g. cycling (17), triathlon (6), swimming (6), running
Height (m) 1.77 0.07 1.64 1.87 (17), weight training (10), other (e.g. kayak, yoga, squash) (10).
Body mass (kg) 75.3 9.2 60.5 92.5 Participant body mass (kg), height (m), fat-free mass (FFM), per-
FFM (kg) 63.5 5.5 55.4 76.5 centage body fat (BC418 Segmental Body Composition Analyzer),
%body fat 15.4 5.5 5.6 24.7
mean resting blood pressure (mmHg) and heart rate (b min−1 )
BMI (kg m2 ) 24.1 2.3 20.9 27.9
Pre-exercise heart rate (b min−1 ) 65 11 45 93 (average of three recordings using automated sphygmomanom-
SBP (mmHg) 126.7 7.9 113 138 etry; Dinamap ProV, UK) were measured. A health questionnaire
DBP (mmHg) 73.4 7.5 63 90 (PAR-Q) was completed to assess fitness to participate; all volun-
Pre-exercise blood lactate (mmol L−1 ) 1.4 0.4 1.0 2.2
teers were healthy non-smokers and were taking no prescribed
VO2 max (L min−1 ) 3.71 0.70 2.54 5.05
Baecke work 2.57 0.58 1.50 3.63 medication.
Baecke leisure 3.20 0.58 2.25 4.00
Baecke sport 4.02 1.56 1.50 7.39 2.2. Physiological measures
Baecke total 9.78 1.94 5.93 14.39

Participants completed a modified standard exercise protocol

is unclear. Regulation of blood borne BDNF may be predominantly
mediated by platelets, which are capable of uptake, storage and
release of the protein [12].
In humans, serum concentrations of BDNF increase transiently
following intense endurance exercise [11,14,28,32,34]. Resistance
exercise also induces an increase in serum BDNF concentration,
which is augmented after resistance training [39] although other
studies investigating either serum [13] or plasma BDNF concen-
trations [8] have not duplicated this finding. Studies measuring
the acute BDNF response to exercise have varied in the exer-
cise task employed, the sample time-points chosen post-exercise
and the BDNF assay used, making comparison between studies
difficult [19]. Increased concentration of serum BDNF following
short periods of exercise in humans may correlate with observed
improvement in short-term learning and memory [38], demon-
strating parallels with studies in rodents [2,35]. These observations
provide support for the hypothesis that BDNF is a key mediator
of the beneficial effects of exercise on brain health and cognitive
function reported in large population studies or meta-analyses [e.g.
1,6,37] and further, that exercise-induced increases in blood BDNF
may be an important component of the neuroprotective nature of
exercise [11].
Previous studies that utilised low and high intensity exercise
bouts on separate occasions have indicated exercise intensity may
determine post-exercise serum [11,27,32,38], and plasma BDNF
concentration [5], in addition such studies have suggested BDNF
returns to baseline levels at either 30 [25,39] or 60 min post-
exercise [31]. The present study set out to measure serum BDNF
concentration during a standardised bout of submaximum exer-
cise and to examine the effect of exhaustive exercise on serum and
plasma concentrations of BDNF to gain insight into its physiological
regulation in blood following exercise.
2. Materials and methods
2.1. Participants
Twenty-nine men were recruited to the current study; how-
ever, patency of intravenous cannulae (protocol below) was only
maintained in twenty-three participants. Therefore experimen-
tal data (mean ± SD) is described for n = 23: age: 28.2 ± 4.8 years;
body mass: 75.3 ± 9.2 kg; height: 1.77 ± 0.07 m; resting heart
rate: 64 ± 11 b min−1 ; systolic blood pressure: 126.6 ± 7.9 mmHg;
diastolic blood pressure: 73.4 ± 7.5 mmHg: further participant
characteristics are provided in Table 1. Participants gave written
consent to take part in the study, which had University Ethics
Committee approval and was conducted in accordance with the
Declaration of Helsinki. Participants arrived to the laboratory 2–3 h
[17] namely 4 × 4 min starting at 90 and finishing at 180 W (30 W
increment every 4 min). After a rest period of approximately 5 min
to allow blood draw and partial recovery participants completed
a 1 min ramp protocol (30 W increment every minute starting
at 150 W) to determine the maximal aerobic power (VO2 max,
L min−1 ) (Monark Ergomedic 874E; Varberg, Sweden). Completion
of the initial 16 min exercise enabled a standard warm up period
and facilitated measurements at a common work rate of 180 W.
Measures of respiratory gas exchange composition were obtained
by a computerised breath-by-breath analysis system (MetaLyzer
3B-Cortex; Leipzig, Germany). Tests were completed in the morn-
ing to minimise influence of circadian rhythms. Maximal aerobic
power (VO2 max) was considered reached at volitional exhaustion,
blood lactate concentration >8.0 mmol L−1 , heart rate ± 10 b min−1
of the age predicted maximum and rating of perceived exertion
(RPE) [4] 18–20, or if cadence fell by 10 rpm, even with strong ver-
bal encouragement (one subject did not attempt the VO2 max test
due to fatigue [195 b min−1 heart rate, 11.3 mmol L−1 blood lactate
concentration, 15 RPE at 180 W]) (Table 2).
2.3. Blood measures
An 18 gauge intra-venous (IV) cannula (Venflon, Becton-
Dickenson [BD]) was inserted into a suitable vein in the antecubital
fossa and flushed with sterile saline (0.9% NaCl IV BP Mini-Plasco,
Braun) to maintain venous access. The cannula was fitted with an
extension tube (1.5 mm × 2.5 mm, 10 cm, Vygon) and three way
tap (Vyclic, Vygon) for ease of blood sampling (BD Vacutainer sys-
tem).
Venous blood samples were taken at baseline (rest), after com-
pletion of the 180 W work rate, immediately following cessation of
the maximal exercise test (0 min) and at 30, 60 and 90 min post-
exercise. Blood samples were drawn into appropriate blood clotting
tubes (CAT, BD Vacutainer), and left to clot at room temperature for
30 min, then at 4 ◦ C for 30 min, before being spun in a refrigerated
centrifuge for 15 min at 2000 × g to extract supernatant which was
immediately frozen at −40 ◦ C. Plasma samples were drawn into
lithium heparin containing tubes (LH, BD Vacutainer), which were
immediately spun in a refrigerated centrifuge at 2500 × g for fif-
teen minutes (Eppendorf 5702R) to extract blood plasma, samples
of which were immediately frozen at −40◦ C. Full plasma profiles
(rest, immediately after maximal exercise and at 30, 60 and 90 min
recovery) were only obtained in 10 of the 23 participants which
could be directly compared with corresponding serum data.
BDNF concentrations were determined by ELISA (CYT 306,
Chemikine, Millipore) with samples and BDNF standards being ana-
lysed in duplicate on 96-well plates. Samples were incubated with
primary antibody at 6 ◦ C for 12 h, serum samples were diluted
40× and plasma samples 2× with sample diluent. Incubation
 M. Gilder et al. / Neuroscience Letters 560 (2014) 137–141
Table 2
Physiological values during submaximal and maximal exercise (mean ± SD).
Measure Submaximal exercise Maximal exercise
Work rate (W) 180 ± 0 315 ± 57
VO2 (L min−1 ) 2.79 ± 0.02 3.71 ± 0.70
%VO2 max 77.6 ± 14.6
HR (b min−1 ) 149 ± 25 185 ± 12
%HRmax 80 ± 10
RPE 14.4 ± 1.6 19.2 ± 1.2
Lactate (mmol L−1 ) 5.2 ± 3.8 12.5 ± 2.6
stages were conducted at room temperature for durations rec-
ommended by the ELISA manufacturer with wash and aspiration
stages conducted by an automated plate washer (ELX50, Biotek).
Colourimetric analysis was conducted using a 96-well plate reader
(EL800, Biotek) and optical densitometry data handled using dedi-
cated software (Gen5, Biotek).
Samples for blood lactate concentration (180 W and 1 min
post-VO2 max test only) were taken by finger prick and mea-
sured by a portable measurement system (Lactate Pro, KDK
Co. Ltd.).
2.4. Statistical methods
Physiological measures were reported as mean ± SD and serum
and plasma BDNF concentrations reported as mean ± SEM. Statisti-
cal analysis was conducted using SPSS. Serum and plasma data were
normally distributed as determined by the Kolmogorov–Smirnov
test. BDNF data was analysed using a two-way repeated measures
ANOVA (alpha at 0.05) with the between subjects factor being the
median split of each variable/factor thought to influence BDNF (age,
height, body mass, FFM, BMI and aerobic fitness (VO2 max)) and
the within-subjects effect being the difference between baseline
concentration and subsequent time points. Comparisons between
high- and low-FFM groups were conducted using an independent-
samples t-test.
3. Results
Mean resting serum BDNF concentration (n = 23) was
11.4 ± 5.0 ng mL−1 and concentrations increased significantly
as a result of steady-rate exercise (180 W) to 16.9 ± 3.7 ng mL−1
(P < 0.01). Immediately post-exhaustive exercise (time 0) BDNF
concentrations were slightly lower (15.1 ± 3.6, P < 0.05) and
declined further during recovery (no significant difference 30 min
post-exercise compared with values at rest). A two-way ANOVA
revealed a significant group-by-time interaction. We conducted a
follow up independent-samples t-test which identified a signifi-
cant difference in serum BDNF between high- and low-FFM groups
(Fig. 1).
Mean resting plasma concentration of BDNF (n = 10) was
89.5 ± 46.4 pg mL−1 . Plasma levels of BDNF increased signifi-
cantly following the test at 0, 30, and 60 min sampling points:
0: 178.0 ± 54.7 pg mL−1 (P < 0.05); 30: 139.1 ± 46.7 (P < 0.05); 60:
128.8 ± 39.3 (P < 0.05) then decreased post-test 90: 89.5 ± 46.4
(NS). Concentration of plasma and serum BDNF ‘peaked’, imme-
diately following maximum exercise (0 min), but plasma BDNF
concentrations were always approximately 100 times lower
than that of serum and took longer to return to near-baseline
concentration. In order to identify responders we calculated
the difference in serum and plasma BDNF concentrations from
rest to maximal exercise. There was little relationship between
these change/delta values (Spearman Rank Correlation = 0.02;
P = 0.95).
139
20
*
Serum BDNF concentration (ng mL-1)
18
16
14
12 High FFM
10 Low FFM
8
6
1 2 3 4 5 6
Time point
Fig. 1. Response of serum BDNF for individuals exhibiting either high or low lev-
els of fat free mass (FFM) respectively at noted time points in the experiment 1
(rest/baseline), 2 (180 W)*, 3 (immediately after the VO2 max test, at time 0), 4 (at
30), 5 (at 60) and 6 (at 90 min post-exercise). Error bars indicate SEM, * indicates
P < 0.05.
4. Discussion
The present study measured a baseline concentration of plasma
BDNF that was lower than some previously reported levels (e.g.
[20]: >2500 pg mL−1 ; [15]: 2230 and [5]: 3377) yet higher than
others (e.g. [40]: 10.3 pg mL−1 ). Both serum and plasma BDNF con-
centrations increased significantly above rest following exhaustive
exercise, returning to concentrations which were not significantly
different from rest by 30 and 90 min post-exercise respectively.
Plasma BDNF levels increased 99% from baseline to post-
maximum exercise values, which was higher than that reported
after exhaustive treadmill exercise in healthy young men (28%, [5])
and lower than that calculated after 4 h ergometer rowing (165%,
[31]). In contrast serum BDNF increased 33%, similar to that calcu-
lated from Rojas Vega et al. [32] at 42%, and a 30% increase reported
by Ferris et al. [11], but less than the 108% increase reported by Cho
et al. [5] during exhaustive treadmill running.
Recently Cho et al. [5] measured parallel concentrations of
serum, plasma and platelet BDNF in healthy young men; in con-
trast with earlier studies which either measured serum or plasma
BDNF concentrations; because measurement of serum levels per
se may not necessarily represent BDNF that is immediately free to
mediate neuroprotective and/or metabolic effects. Since platelets
are unlikely to actively synthesise BDNF but are capable of taking
up the protein [12], it seems reasonable to hypothesise that the
plasma increase post-exercise is BDNF secreted primarily from the
brain [30,31]. The physiological mechanisms underlying the post-
exercise serum BDNF increase are, however, less clear. Changes
in post-exercise serum BDNF may represent BDNF uptake from
the circulation and storage by platelets (for later release or pos-
sible degradation), or an acute increase in platelet number possibly
modulated by splenic contraction, or (given that platelets only
partially release stored BDNF on stimulation [12]) an increase in
platelet reactivity that can occur post-exercise [16,36]. The molec-
ular control of BDNF uptake and release from platelets remains to
be fully elucidated, however, a platelet uptake mechanism leads
to compartmentalised storage in the platelet cytoplasm or secre-
tory granules [18], release being triggered by factors inducing
platelet activation, including thrombin, collagen and shear stress
[36]. It is currently unknown what the principal tissue recipi-
ent of blood–borne BDNF is, but given serum BDNF concentration
increased after maximal exercise by 3.40 ng mL−1 whereas plasma
concentration increased by only 0.09 ng mL−1 (88.5 pg mL−1 ) at the
same time point – it may be that platelets are the major site for
140 M. Gilder et al. / Neuroscience Letters 560 (2014) 137–141
uptake and temporary storage of brain released BDNF following
exercise in humans. Regardless of the origin of circulating BDNF
the present study demonstrates that at all time points (both before
and after exercise) the majority of circulating BDNF was derived
from platelets rather than circulating free in plasma.
We found no relationship between serum BDNF concentration
and the relative exercise intensity during submaximum exercise
(i.e. at 180 W). Similarly we were unable to demonstrate a relation-
ship between serum BDNF and blood lactate values post-maximum
exercise [11]. Nevertheless results of the present study agree
closely with earlier work with respect to identifying a submaxi-
mum exercise intensity which results in a significant increase in
BDNF concentration namely: 77.6 ± 14.6% VO2 max and 14.4 ± 1.6
RPE (Table 2) compared with 75.2 and 14.2 ± 0.4, present study vs.
Ferris et al. [11] respectively. Thus if BDNF does exert neuropro-
tective effects the present study supports the hypothesis that it is
not necessary to engage in exhaustive exercise in order to elevate
circulating levels of BDNF. Indeed future work could usefully iden-
tify a minimum exercise intensity leading to significant increases
in BDNF concentration above rest.
The present study alluded to a very fast recovery mecha-
nism for BDNF immediately upon cessation of exercise; namely
serum BDNF concentration was 16.9 ± 3.7 at 180 W and slightly
lower, 15.1 ± 3.6 ng mL−1 , at termination of exhaustive exercise
(315 ± 57 W), some 7–10 min later. In addition a unique finding of
the present study was the demonstration of a significant group-by-
time interaction for the FFM (Fig. 1) (this pattern of response was
not duplicated by any other variable we investigated). The greater
serum BDNF response to exercise demonstrated by the high-FFM
group may be a reflection of an augmented response to resistance
training [39], which was a feature of a number of individuals’ train-
ing programmes. Similarly the faster return of serum BDNF levels
to a baseline concentration may reflect differences in both aerobic
[28] and resistance training status [39] for high- compared with
low-FFM groups.
We speculate that trained skeletal muscle (comprising a large
proportion of the FFM), together with an elevated aerobic fitness
may be significant factors in both the BDNF response to exercise and
it’s time course for return to baseline concentrations post-exercise.
The present study has some limitations, the small number
of complete plasma profiles obtained restricts the investigation
between plasma BDNF levels and measures of FFM and cardio-
respiratory fitness due to lack of statistical power. The experiment
did not directly measure the platelet content of BDNF nor inves-
tigate how platelet BDNF is compartmentalised within the cell,
questions which still need to be addressed. Nonetheless, it is
intriguing to consider that the localisation of BDNF in platelets fol-
lowing exercise may be a mechanism which regulates the release
of BDNF from the brain to the blood. Further work is required to
investigate the physiological function of this regulation (including
interactions with levels of aerobic fitness and FFM) and the fate of
BDNF within platelets, both at rest and following exercise.
Conflict of interest
The authors have no conflict of interest. The work described
herein was University sponsored research. Funding sources were
not involved in the design of the experiments, the exploitation of
results, or the decision to publish them.
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