11
Journal of Exercise Physiologyonline
Volume 15 Number 4 August 2012
Editor-in-Chief
Tommy Boone, PhD, MBA
Review Board
Todd Astorino,
Deepmala
Agarwal,
PhD PhD
JulienAstorino,
Todd
Baker, PhD
PhD
Steve Brock,
Julien
Baker, PhD
PhD
Lance Brock,
Steve
Dalleck,
PhD
PhD
Eric Goulet,
Lance
Dalleck,
PhD
PhD
Robert
Eric
Goulet,
Gotshall,
PhD PhD
Alexander
Robert
Gotshall,
Hutchison,
PhD PhD
M. Knight-Maloney,
Alexander
Hutchison,
PhD
PhD
LenKnight-Maloney,
M.
Kravitz, PhD PhD
James
Len
Kravitz,
Laskin,
PhD
PhD
Yit AunLaskin,
James
Lim, PhD
PhD
Lonnie
Yit
Aun Lowery,
Lim, PhD
PhD
Derek Marks,
Lonnie
Lowery,
PhD
PhD
CristineMarks,
Derek
Mermier,
PhDPhD
Robert Robergs,
Cristine
Mermier,PhD
PhD
ChantalRobergs,
Robert
Vella, PhD
PhD
Dale Wagner,
Chantal
Vella, PhD
PhD
FrankWagner,
Dale
Wyatt, PhD
PhD
Ben Zhou,
Frank
Wyatt,
PhD
PhD
Ben Zhou, PhD
Official Research Journal of
Official
the American
ResearchSociety
Journalof
of the
Exercise
American
Physiologists
Society of
Exercise Physiologists
ISSN 1097-9751
ISSN 1097-9751
JEPonline
Effects of Endurance Exercise Training on BrainDerived Neurotrophic Factor
James S. Williams1, Lee T. Ferris2
1Department
of Health and Human Performance, Texas State
University, San Marcos, Texas, 2Department of Physiology, Texas
Tech University Health Sciences Center, Lubbock, Texas
ABSTRACT
Williams, JS, Ferris, LT. Effects of Endurance Exercise Training on
Brain-Derived Neurotrophic Factor. JEPonline 2012;15(4):11-17. As
a member of the growth factor family, brain-derived neurotrophic
factor (BDNF) has been identified as an important mediator of
neuronal health. The purpose of this investigation was to determine
the effects of an endurance training program on basal levels of BDNF.
Eighteen physically active subjects completed a 12-wk supervised
jogging class (3x/wk, 30 min/session, 65-70% HR max). A graded
exercise test was conducted before and after the training program to
determine maximal oxygen consumption (VO2 max) and maximal work
rate (WR max) on a cycle ergometer. Blood samples for basal serum
BDNF and cortisol (COR) were also obtained before, at the mid-point,
and after the training program. Training resulted in a significant
increase (P<0.05) in VO2 max and WR max. Both BDNF and COR
were unchanged (P>0.05) in response to the training program. It was
concluded that aerobic exercise training of this intensity, frequency,
and duration did not provide an adequate training stimulus to result in
a significant upregulation of basal BDNF.
Key Words: Growth Factors, Aerobic Training, Neuronal Health
12
INTRODUCTION
Brain-derived neurotrophic factor (BDNF) is an endogenous growth factor that plays a vital role in
neuronal health. The binding of BDNF to a tyrosine kinase receptor results in neuronal survival,
differentiation, and the promotion of synaptic transmission and long-term potentiation (2). The BDNF
treatment of hippocampal slices from BDNF-knockout mice reverses deficits in long-term potentiation
as well as improves basal synaptic transmission (9). The BDNF is also protective against ischemic
insults and promotes neurogenesis (4). It is found and made in many locations throughout the body,
especially the visceral epithelial cells, smooth and skeletal muscle fibers, and the brain and spinal
cord (7,8).
The potential of exercise to affect neural function is becoming increasingly recognized. An acute bout
of exercise has been shown to increase BDNF concentrations in humans (5,6,10). Furthermore, it
appears that the increase in BDNF concentration in response to acute exercise is intensity-dependent
(5,10). However, data describing the basal response of BDNF to an endurance exercise training
program are unclear and lacking in humans (3,12,14). The purpose of this study was to determine the
effects of a moderate intensity 12-wk jogging program on basal BDNF levels in young healthy human
subjects.
METHODS
Subjects
The study population consisted of eighteen subjects (3 males and 15 females; age 20.0±0.3 yr; height
167.6±2.4 cm; weight 61.8±2.4 kg; BMI 21.9±0.4 kg/m2; mean ± SE) who were physically active, but
not engaged in competitive sports. The participants were members of a formal university jogging
class. Based on a detailed health history questionnaire, all subjects were nonsmokers and free of
cardiopulmonary, metabolic, and musculoskeletal diseases. Thus, the subjects were in good health
and free of any physical condition placing them at risk for participation in the study. The research
design and data collection procedures were approved by the institutional review board. All subjects
signed an informed consent form.
Procedures
A summary of the study timeline and procedures is shown in Figure 1. Participation in the study
required three visits to the laboratory. During the first and third visits, the subjects performed a graded
exercise test (GXT) on a stationary cycle. Prior to the GXT, blood samples were obtained for the
determination of basal serum BDNF and cortisol (COR) levels. During the second visit, at the
midpoint of the 12-wk training program, BDNF and COR levels were again obtained. All testing was
performed at the same time of the day.
GXT Procedures
Testing was performed on an electronically-braked cycle ergometer (Lode, Corival). After a 5-min
warm-up of unloaded cycling, the workload was set at 50 W and incremented by 25 W each minute to
volitional fatigue. Pedal frequency was maintained at 70 rpm. Oxygen consumption (VO 2) and work
rate (WR) were determined during the GXT on a breath-by-breath basis with samples averaged for
30-sec intervals (MedGraphics, CPX/D). The highest 30-sec average was defined as maximum.
Volume and gas calibration of the metabolic system were performed before each test in accordance
with the manufacturer’s specifications. Blood pressure was monitored during the GXT via
auscultation. Heart rate and rhythm were obtained via standard electrocardiography (Quinton
Instruments, Model 4000). The subjects were instructed to avoid strenuous exercise for 24 hrs and
food and caffeine for 3 hrs before each GXT.
13
Laboratory Visit #1:


Laboratory Visit #3:


Medical history, informed
consent and blood draw
Subjects perform graded
exercise test (GXT)



Jog 3x/wk
30 min/session
65-70% HR max
1st 6-wk period



Blood draw
Subjects perform graded
exercise test (GXT)
Jog 3x/wk
30 min/session
65-70% HR max
2nd 6-wk period
Laboratory Visit #2:

Blood draw
Figure 1. Summary timeline for the study procedures.
Blood Sampling and Analysis
A 10 ml sample of blood was withdrawn from the antecubital vein for the determination of basal
serum BDNF and COR levels. The blood was allowed to clot (1 hr) and then centrifuged for 12 min at
1300 rcf (Eppendorf, Model 5804). The supernatant was decanted and stored in a -80 °C freezer until
analysis. Serum BDNF was assayed via a sandwich ELISA kit (Chemikine). The sensitivity as
reported in the ELISA kit literature was 7.8 pg.mL-1. Serum COR was assayed via radioimmunoassay
(Diagnostic Products). The reported sensitivity was 0.2 g/dL.
Exercise Training Procedures
The participants jogged outdoors for 30 min/exercise session, 3x/wk, for 12 wk at an exercise heart
rate range that corresponded to 65-70% HR max as determined from the GXT. All the participants
wore a heart rate monitor (Polar A1) that enabled them to maintain a jogging pace within the
prescribed heart rate range. The training sessions were monitored for attendance and supervised by
experienced exercise instructors.
Statistical Analyses
Differences between pre- and post-exercise training VO2 max and WR max values were analyzed
using paired t-tests. Serum BDNF and COR values over the course of the study were analyzed using
14
repeated measures ANOVA. Significant main effects were further analyzed with Student-Newman
post hoc tests. The association between the pre- and post-exercise training changes in basal serum
BDNF and COR and changes in VO2 max and WR max were examined with Pearson correlation
coefficients. The level of significance was set at P<0.05. All values are reported as mean + SE.
Statistical analyses were conducted using SigmaStat for Windows (Jandel Scientific Software,
SPSS).
RESULTS
Analysis of the attendance records for the training group demonstrated an 87.5% compliance rate
(i.e., 567 exercise sessions were completed of a possible 648). Post-training VO2 max and WR max
were significantly increased following the 12-wk jogging program compared to pre-training values
(4.8% and 7.3%, respectively) (Figure 2). The baseline mean VO2 max was 33.8 mL·kg·min-1, which
increased to 35.4 mL·kg·min-1 post-training (P<0.01). The baseline mean WR max was 168.3 W,
which increased to 180.5 W post-training (P<0.001). Mean basal values during the time course of the
training program (beginning, midpoint, and endpoint) for BDNF and COR are shown in Figure 3. The
mean basal BDNF values for the three measurement points were 14180.7, 15064.7, and 14820.8
pg.mL-1, respectively. There were no significant differences among the three time points (P>0.05).
The mean basal COR values for the three measurement points were 26.1, 20.4, and 25.7 g/dL,
respectively. There were no significant differences among the three time points (P>0.05). There was
no significant correlation between the change in BDNF and the change in VO2 max (R = 0.32,
P>0.05), nor was there was there a significant correlation between the change in BDNF and the
change in WR max (R = 0.050, P>0.05). Similarly, there was no significant correlation between the
change in COR and either the change in VO2 max (R = 0.010, P>0.05) or the change in WR max (R =
0.10, P>0.05).
*
200
180
*
35
Work Rate (Watts)
VO2max (mL O2/kg/min)
40
160
140
120
100
80
60
40
20
30
0
Beginning
Endpoint
Beginning
Endpoint
Figure 2. Maximal oxygen consumption, VO2 max, (left panel) and maximal work rate, WR max, (right
panel) before and after the 12-wk endurance training program. Values are means  SE;
*Significantly different from baseline; P<0.01.
15
16000
BDNF (pg/ml)
14000
12000
10000
8000
6000
4000
2000
0
35
Cortisol (ug/dl)
30
25
20
15
10
5
0
Beginning
Midpoint
Endpoint
Figure 3. Serum BDNF (top panel) and COR (lower panel) concentrations before, at the midpoint, and
after the 12-wk endurance training program. Values are means  SE; P>0.05.
DISCUSSION
The primary purpose of this study was to determine the effects of a 12-wk endurance exercise
program on BDNF concentrations in humans. Our key indicators of a training effect, VO 2 max and WR
max, were significantly higher post-training compared to baseline suggesting that a training effect,
however small, was achieved. The endurance training program did not significantly alter basal levels
of BDNF.
16
BDNF and COR Responses
Our findings are in contrast to those of Baker et al. (1) Seifert et al. (14), and Zoldac et al. (15) where
basal BDNF was elevated following an aerobic training program. The differences may be explained
by the higher intensity training protocol (i.e., greater training frequency and percentage of heart rate
or VO2max) used in the earlier studies. In addition, Schiffer et al. (13) has shown that infusion of
lactate at rest increases BDNF concentrations, which supports the idea that higher intensity aerobic
training may be necessary to upregulate basal BDNF. Previous data regarding the response to an
acute bout of exercise suggests that an increase in BDNF is dependent upon the exercise intensity as
well (5,10), and this finding may be similar for chronic exercise training. Castellano and White (3)
were unable to demonstrate a significant increase in basal BDNF concentrations following either 4 or
8 wks of aerobic training (3x/week at 60% VO2 peak) in controls and multiple sclerosis patients.
Schiffer et al. (12) demonstrated a 20% decline in basal BDNF in subjects that trained for 45 min,
3x/week for 12 wks at 80% of the HR at lactate threshold. The training intensity of these studies is
more aligned with that of the present study. Basal COR levels were also measured from blood
samples taken at the beginning, middle, and end of the training protocol while the subjects were
resting. Stress, perhaps via a cortisol-mediated mechanism is thought to have deleterious effects on
neural tissue and a dose-dependent decrease of BDNF in rodents following corticosterone
administration has been demonstrated (11). The chronic training from this protocol resulted in no
significant changes in basal COR levels and could not have affected our BDNF responses.
CONCLUSIONS
A 12-wk aerobic training program of moderate intensity completed by healthy subjects did not result
in an increase in basal BDNF concentrations. It is possible that a higher training volume (i.e.,
intensity, frequency, and duration) is needed to elicit favorable results with respect to the regulation of
this neurotrophin during exercise. Future studies should consider the differential effects of training
volume with respect to both aerobic and strength training programs.
Address for correspondence: J.S. Williams, PhD, Health and Human Performance, Texas State
University, 601 University Drive, San Marcos, TX, 512-245-1970, 512-245-8678 (fax),
jw88@txstate.edu.
REFERENCES
1. Baker LD, Frank LL, et al. Effects of aerobic exercise on mild cognitive impairment. Arch
Neurol. 2010;67:71-79.
2. Blum R and Konnerth A. Neurotrophin-mediated rapid signaling in the central nervous system:
mechanisms and functions. Physiology (Bethesda). 2005;20:70-78.
3. Castellano V and White LJ. Serum-brain derived neurotrophic factor response to aerobic
exercise in multiple sclerosis. J Neurol Sci. 2008;269:85-91.
4. Cotman CW and Engesser-Cesar C. Exercise enhances and protects brain function. Exerc
Sport Sci Rev. 2002;30:75-79.
17
5. Ferris LT, Williams JS, et al. The effect of acute exercise on brain-derived neurotrophic factor
levels and cognitive function. Med Sci Sports Exerc. 2007; 39:728-734.
6. Gold S M, Schulz KH, et al. Basal serum levels and reactivity of nerve growth factor and brainderived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. J
Neuroimmunol. 2003;138:99-105.
7. Hutchinson K J, Gomez-Pinilla F, et al. Three exercise paradigms differentially improve
sensory recovery after spinal cord contusion in rats. Brain. 2004;127:1403-1414.
8. Lommatzsch M, Braun A, et al. (1999). Abundant production of brain-derived neurotrophic
factor by adult visceral epithelia. Implications for paracrine and target-derived Neurotrophic
functions. Am J Pathol. 1999;155:1183-1193.
9. Patterson, SL, Abel T, et al. (1996). Recombinant BDNF rescues deficits in basal synaptic
transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996;16:1137-1145.
10. Rojas Vega S, Struder HK, et al. Acute BDNF and cortisol response to low intensity exercise
and following ramp incremental exercise to exhaustion in humans. Brain Res. 2006;1121:5968.
11. Schaaf M J, Hoetelmans RW, et al. Corticosterone regulates expression of BDNF and trkB but
not NT-3 and trkC mRNA in the rat hippocampus. J Neurosci Res. 1997;48:334-341.
12. Schiffer T, Schulte S, et al. Effects of strength and endurance training on brain-derived
neurotrophic factor and insulin-like growth factor in humans. Horm Metab Res. 2009;41:250254.
13. Schiffer T, Schulte S, et al. Lactate infusion at rest increases BDNF blood concentration in
humans. Neurosci Lett. 2011;488:234-237.
14. Seifert T, Brassard P, et al. Endurance training enhances BDNF release from the human
brain. Am J Physiol Regul Integr Comp Physiol. 2010;298:372-377.
15. Zoldac JA, Pilic A, et al. Endurance training increases plasma brain-derived neurotrophic
factor concentration in young health men. J Physiol Pharmacol. 2008;59:119-132.
Disclaimer
The opinions expressed in JEPonline are those of the authors and are not attributable to JEPonline,
the editorial staff or the ASEP organization.