Nishi 7, Kita 11-jo, Kita-ku, Sapporo City, Hokkaido Japan ** Clinic of Tsuruta Orthopaedic Surgery

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1. Introduction

It is most likely that a specifi c gene decides human physical performance. The fi rst relevant report was made by Montgomery et al., in which they noted that angiotensin I converting enzyme (ACE) gene insertion (I) / deletion (D) polymorphism affects human physical performance (Montgomery et al., 1998). ACE gene I/D polymorphism is encoded by

two variants: the insertion allele (I allele) and the deletion allele (D allele), which are identifi ed by the presence or absence of 287- base pair alu sequence on intron16. ACE activity in blood and tissue is lower in I allele homozygous (I/I) than in D allele homozygous (D/D), and heterozygous (I/D) stands in the middle (Rigat et al., 1990; Higashimori et al., 1993; Danser et al., 1995).

ACE is a key enzyme in the renin angiotensin (RA)

Association of Angiotensin I Converting Enzyme Gene

Insertion/Deletion Polymorphism with the Renin-angiotensin System and Blood Pressure Response during a Single Bout of Exercise

Takuro Tobina *,****, Ryoma Michishita**, Zhang Bo***, Keijiro Saku***, Munehoro Shindo****, Hiroaki Tanaka**** and Akira Kiyonaga****

*Graduate School of Education, Hokkaido University Nishi 7, Kita 11-jo, Kita-ku, Sapporo City, Hokkaido 060-0811 Japan

tobitaku@ck9.so-net.ne.jp

**Clinic of Tsuruta Orthopaedic Surgery

174-8 Kamitokigawa, Ushidu oaza, Ogori gun, Saga 849-0305 Japan

***Department of Cardiology, Fukuoka University School of Medicine 7-45-1 Nanakuma, Jonan-ku, Fukuoka City, Fukuoka 814-0180 Japan

****Faculty of Sports and Health Science, Fukuoka University 8-19-1 Nanakuma, Jonan-ku, Fukuoka City, Fukuoka 814-0141 Japan

[Received May 20, 2005 ; Accepted July 20, 2005]

We investigated the association between Angiotensin I converting enzyme (ACE) gene insertion (I) /deletion (D) polymorphism and responses of hormonal factors related to vasoconstriction and volume loading of heart, enzyme activities of Renin-Angiotensin system, blood pressure and heart rate during a single bout of exercise. Six insertion homozygous (I/I) and 6 deletion homozygous (D/D) young men participated in this study. Subjects performed a multi-load exercise test at 1/2 lactate threshold (LT), LT, onset blood lactate accumulation (OBLA), and middle point of OBLA to maximum exercise load (OBLA-Peak) intensities. The duration of intensities was 10 minutes. Blood samples, blood pressure and heart rate were obtained at rest, in the last 2 minutes of every intensity, and 3 minutes after fi nishing exercise (recovery). However the plasma ACE activity in I/I was lower than that in D/D at rest, during exercise and recovery, and Angiotensin II was no different in I/I and D/D. Furthermore, there were no differences in plasma Renin activity, Angiotensin I, plasma aldosterone concentration, atrial natriuretic peptide, brain natriuretic peptide, adrenaline, noradrenalin, dopamine, systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate and double product at rest, during exercise and recovery.

No relationship between plasma ACE activity and Angiotensin II existed, but plasma Angiotensin I and Angiotensin II had a positive correlation in I/I and D/D. This data suggests that the ACE gene I/D polymorphism is not associated with plasma Angiotensin II concentration during a single session of exercise.

Keywords: Angiotensin I converting enzyme, Polymorphism, Exercise

[International Journal of Sport and Health Science Vol.4, 465-471, 2006]

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system which regulates blood pressure. It converts angiotensin I (Ang I) to strong vasoconstrictor angiotensin II (Ang II). In addition, Ang II stimulates aldosterone secretion in the adrenal glands, increasing blood pressure via another pathway as a result of facilitating retention of water and sodium.

Our previous study indicated that a mild intensity exercise therapy for hypertensive patients effi ciently reduced blood pressure but that still there were inter-individual differences in the effect. Patients with good response in the therapy had higher cardiac index, serum Na/K ratio and lower total peripheral resistance in pre-training while patients who showed poor response had higher peripheral resistance (Kinoshita et al., 1988). We also reported that moderate hypertensive I/I patients in ACE gene I/D polymorphism observed good response in the exercise therapy (Zhang et al., 2002). Our recent study examining the relationship between change of blood pressure and heart rate (HR) during incremental exercise and ACE gene I/D polymorphism observed higher blood lactate acid concentration (LA), systolic blood pressure (SBP), and double product (DP) at double product breaking point (DPBP) in I/I than in D/D (Kiyonaga et al., 1999). Friedl et al. have reported that, at maximum exercise and three minutes after exercise, diastolic blood pressure (DBP) in D/D is higher than in I/I while heart rate (HR) in D/D is lower than I/I (Friedl et al., 1996). Also, they have reported that atrial natriuretic peptide (ANP) in D/D is higher than I/I after maximum exercise (Friedl et al., 1998). Those studies suggested that ACE gene I/D polymorphism might infl uence circulation response during exercise.

Yet, what caused the differences was unknown.

A C E g e n e I / D p o l y m o r p h i s m d e c i d e s approximately 50% of serum ACE activity. It is likely that it affects circulating response during exercise by regulating Ang II production. I/I has lower serum ACE activity than D/D so that it may produce less Ang II. The result of lower DBP in I/I than D/D during and after exercise may refl ect less production of Ang II.

The aim of this study is to investigate factors which cause differences in the change of blood pressure during a single bout of exercise in I/I and D/D of ACE gene I/D polymorphism. We compared I/I and D/D in hormones relevant to vasoconstriction and volume loading of heart (Lang et al., 1985), enzyme activity in the RA system, and change of

blood pressure and HR.

2. Method 2.1. Subjects

Twelve young Japanese males out of 381 members of our cohort who were I/I or D/D participated in this study. We thoroughly explained the signifi cance, content, contribution to society, and method of the study before obtaining their consent. The present study was approved by the Ethics Committee on Medicine at Fukuoka University.

2.2. Genotyping of ACE gene I/D polymorphism We extracted genomic DNA from peripheral blood leukocytes and amplifi ed them by a polymerase chain reaction (PCR). Then, we detached I allele and D allele of ACE gene fragments of the PCR product by agarose gel electrophoresis and stained them with ethidium bromide for thirty minutes. Then, we took pictures of the agarose gel under ultraviolet light to determine ACE gene I/D polymorphism (Zhang et al., 2002).

2.3 Deciding Exercise Load

The subjects performed an incremental exercise test in upright position using an electric bicycle ergometer (Rehcor: Lode, Netherlands) in a thermostatic room with a room temperature of 21 ℃.

Exercise load was gradually increased by 20 watts every 4 minutes after applying 0 watts for 4 minutes until reaching 4mmol/l of LA. From one minute before the end of each load, we started sampling blood from their earlobes to measure LA by the immobilized enzyme method (BIOSEN 5040: EKF, Germany) (Davison et al., 2000).

To measure maximum exercise load (peak) and maximum oxygen consumption (VTo measure maximum exercise load (peak) and To measure maximum exercise load (peak) and 44 o2max), we Vo2max), we increased the load to 10 watts/min from the next V load after exceeding 4mmol/l of LA and made the subjects continue exercising until they became utterly exhausted. All subjects satisfi ed at least three of the following fi ve criteria for utter exhaustion. The criteria were: 1) leveling off of oxygen intake; 2) more than 8mmol/l of LA after exercise; 3) leveling off of HR; 4) more than 18 in the ratings of perceived exertion (RPE); and 5) more than 1.15 in the

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respiratory exchange ratio (ACSM, 2001).

To measure V4

respiratory exchange ratio (ACSM, 2001).4 respiratory exchange ratio (ACSM, 2001).

o Vo

V 2max, we took expired gas during exercise every 1 minute by the douglas bag method.

Ventilation volume (VE) was measured using a two-barrel respirometer (CR-20: Fukuda Ilika Research Laboratory, Japan) and O2 and CO2 concentrations were measured using a spectrograph (Acro-1000: Arco System, Japan).

Lactate threshold (LT) and the workload at 4mmol/l of LA (OBLA) were decided by fi ve technicians. Each technician assessed the steep-increase point of LA and the load equivalent to 4mmol/l of LA from visual inspection of graphical plots of LA versus workload. LT and OBLA were the means of three values out of fi ve, which excluded the maximum and the minimum obtained from the subjects. We calculated 1/2 LT, middle intensity of OBLA and maximum exercise load (OBLA-Peak).

These four workloads were used as the exercise intensities for the present study.

2.4. Exercise Test

All the subjects arrived at the laboratory at 8:30 am on the test day after fasting at least twelve hours.

After resting for thirty minutes at the laboratory, they started the exercise test using an electric bicycle ergometer. The duration of each intensity was 10 minutes.

Just before the start of the exercise of each intensity, blood samples were taken from the indwelling brachial vein. During exercise, blood samples were also obtained at two minutes before the end of each intensity and three minutes after the end of exercise (recovery). Those blood samples were used to measure serum renin activity (PRA), Ang I, Ang II, serum aldosterone concentration (PAC), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) by radioimmunoassay, serum ACE activity by the Kasahara method (Kasahara

et al., 1982), and adrenaline (Ad), noradrenaline (Nor), and dopamine(DA) by high-pressure liquid chromatography.

We measured SBP, DBP, and HR at rest, at one minute before the end of each intensity, and during recovery using an exercise load blood pressure monitor device (Tango: Sun Tech Instruments, USA) and calculated mean blood pressure (MBP) and DP.

We also took the last one-minute of expired gas in each intensity by the douglas bag method to seek V4

each intensity by the douglas bag method to seek 4 each intensity by the douglas bag method to seek

o Vo

V 2 and calculate %V4

each intensity by the douglas bag method to seek 4 each intensity by the douglas bag method to seek

o Vo

V 2max. Further, we took blood samples from earlobes at one minute before the end of each intensity to measure LA.

3. Statistical analysis

We used Statview (SAS, USA) for the statistical software. Man Whitney’s U-test was used to compare characteristics, hormone concentration, enzyme activity, blood pressure, and HR at rest. The values of %V4

enzyme activity, blood pressure, and HR at rest. The 4 enzyme activity, blood pressure, and HR at rest. The o2max, hormone concentration, enzyme Vo2max, hormone concentration, enzyme activity, blood pressure, HR and LA during exercise V and at recovery were log-translated in statistical analysis, and two-way ANOVA with repeated measures was used to examine differences in I/I and D/D. P-values of 0.05 or less were considered to be signifi cant.

4. Result

4.1. Characteristics and hormone concentration, enzyme activity, blood pressure and HR at rest

The age of I/I was signifi cantly higher than that of D/D but height, weight, body mass index (BMI), and V4

of D/D but height, weight, body mass index (BMI), 4 of D/D but height, weight, body mass index (BMI),

o Vo

V 2max were not signifi cantly different (Table 1).

Although I/I was signifi cantly lower than D/D in serum ACE activity at rest, no difference was found in Ang II, RRA, Ang I, PAC, ANP, BNP, Ad, Nor, DA, SBP, DBP, MBP, HR and DP between the genotypes (Table 2).

4.2. Change of hormone concentration, enzyme activity, blood pressure and HR during exercise and recovery

There was no difference in %VVoV4o2max and LA during exercise between the genotypes (Table 3).

The subjects who could continue exercising for ten minutes in OBLA-Peak were four of six in I/I and

Table 1 Characteristics of the subjects.

BMI = body mass index; VVoVo2max = maximum oxygen uptake; LA = lactic acid. Values are given as mean ± SD.

P-value Age (year)

Height (cm) Weight (kg) BMIVo2max (ml/min/kg)

170.325.2 68.723.7 41.4

3.24.0 4.51.8 7.0

174.021.5 68.322.5 41.9

1.45.4 8.42.4 6.6

0.030.20 0.750.34 0.87 I/I Genotype D/D

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one of six in D/D.

However, serum ACE activity of I/I was signifi cantly lower than that of D/D during exercise and recovery (Figure 1). Ang II was not different between I/I and D/D during exercise and at recovery like at rest (Figure 2). Ang I (Figure 2) PRA, PAC, Ad, Nor, DA, ANP, BNP (Table 4), HR, DP (Table 5), and

blood pressure (Figure 3) also showed no signifi cant difference between the genotypes.

No correlation was observed between serum ACE activity and Ang II in I/I and D/D (Figure 4), but a positive correlation was observed between Ang I and Ang II (Figure 5).

5. Discussion

We hypothesized that I/I of ACE gene I/D polymorphism with lower serum ACE activity might have lower Ang II concentration than D/D during a single bout of exercise. The present study confi rmed that ACE activity in I/I was signifi cantly lower than in D/D at rest, during and after exercise (Rigat et al., 1990; Higashimori et al., 1993; Woods et al., 2003).

Contrary to our hypothesis, Ang II concentration recognized no difference between I/I and D/D at rest, during and after exercise.

Friedl et al., however, reported that DBP at maximum exercise and three minutes after maximum exercise was lower in I/I than in D/D and that HR was higher in I/I than in D/D (Friedl et al., 1996).

In the present study, there was no difference in the change of DBP and HR between the genotypes. Also, there was no difference between I/I and D/D during exercise not only in Ang II but PRA, Ang I, PAC, Ad, Nor, DA, which are enzymes or hormones that increase systemic vascular resistance. The results negated the possibility of infl uence of ACE gene I/D polymorphism on the change of DBP during exercise.

A previous study using a pharmacological method as Ang I infusion found no difference between I/I

PRA (ng/ml/hour) Ang I (pg/ml) ACE (IU/I/37 ) Ang II (pg/ml) PAC (pg/ml) ANP (pg/ml) BNP (pg/ml) Ad (pg/ml) Nor (pg/ml) DA (pg/ml) SBP (mmHg) DBP (mmHg) MBP (mmHg) HR (beat/min) DP

P-value 0.630.11 P < 0.01 0.420.58 0.940.63 0.750.15 0.420.75 0.690.87 0.260.20 Genotype

2.00 0.64 129.83 29.94

9.75 1.60 9.00 3.29 108.83 22.72

10.17 0.41 2.63 1.55 39.00 17.72 349.17 120.32

8.67 4.46 123.94 8.92 77.81 11.45 93.19 10.05 70.33 7.00

8714 1045

I/I 2.40 1.28

175.17 58.28 18.48 3.76 11.17 5.15 126.50 56.19

10.33 0.82 3.05 2.38 48.50 50.07 458.00 120.89

11.50 6.47 123.47 11.65

80.72 15.54 94.97 14.02 67.00 9.47

8332 1915 D/D

Table 2 Hormonal factors relate to vasoconstriction and stroke volume, enzyme activities of renin-angiotensin system, blood pressure, heart rate and double product at rest.

PRA = plasma Renin activity; Ang I = Angiotensin I; ACE

= Angiotensin I converting enzyme; AngII = Angiotensin II; PAC = plasma aldosterone concentration; ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; Ad = adrenaline; Nor = noradrenalin; DA = dopamine; SBP = systolic blood pressure; DBP = diastolic blood pressure;

MBP = mean blood pressure; HR = heart rate; DP = double product. Values are given as mean ±SD.

Recovery P-value 1/2 LT LT OBLA

%Vo2max

(%) I/I 0.29

D/D 27.77

6.70 24.27 9.00

46.23 8.19 38.95 9.73

67.92 5.57 68.93 12.17

89.93 2.49 85.03 9.16

(mmol/l)LA 0.07

9.422.42 7.540.63 I/I

D/D 1.340.47 1.070.32

2.280.79 1.680.46

5.191.56 4.160.52

9.821.34 7.641.15 OBLA-Peak Exercise intensities

Table 3 A percentage of maximal oxygen consumption and blood lactate concentration during exercise and recovery.

%VVoVo2max = percentage of maximum oxygen uptake; LA = lactic aid. One of six in insertion homozygous and four of six in deletion homozygous could perform OBLA-Peak intensity completely. Values are given as mean±SD.

ACE(IU/I/37)

6 8 10 12 14 16 18 20 22 24 26

Recovery OBLA-Peak

OBLA LT

1/2LT

Figure 1 Changes in Angiotensin I converting enzyme (ACE) activities during exercise and recovery in insertion (○) and deletion (●) homozygous of ACE gene insertion/deletion polymorphism. One of six in insertion homozygous and four of six in deletion homozygous could perform OBLA-Peak intensity completely. Log translated values were used for 2 way ANOVA repeated measure (p

way ANOVA repeated measure (p

way ANOVA repeated measure ( <0.01). Data are shown as mean and SD.

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and D/D in Ang II production (Lachurie et al., 1995).

Despite the difference in the method of circulation system activation, the present study verifi ed the same fi nding.

This study did not fi nd differences between I/I and D/D in ANP change during and after exercise. Friedl et al. (1998) proposed that D/D might produce more Ang II which stimulates ANP secretion so that ANP should be higher in D/D than in I/I. Nevertheless, in the present study, no difference was recognized in the change of Ang II by exercise between I/I and D/D.

It may be explained that this gene polymorphism was not infl uential in the change of ANP. Woods et al. also reported that blood Ang II concentration at 70%V4

et al. also reported that blood Ang II concentration 4 et al. also reported that blood Ang II concentration

o Vo

V 2max intensity did not relate to ACE gene I/D polymorphism (Woods et al., 2003). We further found that ACE gene I/D polymorphism was not

a factor which affects Ang II concentration during exercise in low intensity (less than LT) and high intensity (OBLA-Peak) exercise, and clarifi ed that

0 20 40 60 80 100 120 140 160 180

AngII(pg/ml)AngI(pg/ml)

200 400 600 800 1000 1200 1400 1600

0

Recovery OBLA-Peak

OBLA LT

1/2 LT

Recovery OBLA-Peak

OBLA LT

1/2 LT

Figure 2 Changes in Angiotensin I (Ang I) and Angiotensin II (Ang II) concentration during exercise and recovery insertion (○) and deletion (●) homozygous of Angiotensin I converting enzyme gene insertion/deletion polymorphism.

One of six in insertion homozygous and four of six in deletion homozygous could perform OBLA-Peak intensity completely. Log translated values were used for 2 way ANOVA repeated measure (AngI; p=0.51, Ang II; p=0.99).

Data are shown as mean and SD.

PRA (pg/ml/h)

I/I D/D

Ad (pg/ml)

BNP (pg/ml) (pg/ml)ANP (pg/ml)PAC

(pg/ml)Nor

(pg/ml)DA I/I D/D

I/I D/D

I/I D/D

I/I D/D

I/I D/D

I/I D/D

7.872.70 11.37 6.74 333.33 118.60 366.67 88.24 231.50 172.78 198.67 51.59 1541.67 332.63 1712.00 485.30 41.00 14.97 53.83 24.36 52.17 44.31 27.50 13.19 6.055.53 5.235.10 Recovery

0.71

0.47

0.15

0.97 0.52

0.25

0.24 P-value 2.580.99

2.921.50 151.67 40.21 170.00 55.14 45.50 14.90 62.50 48.73 370.50 152.00 588.83 228.33 9.505.28 14.50 7.01 11.67 2.66 10.83 2.04 2.571.39 3.753.82 1/2 LT

3.471.19 3.131.22 188.33 70.83 208.33 74.68 84.00 21.54 107.33 51.20 479.00 158.27 617.67 189.22 13.50 2.43 16.00 4.38 12.00 3.35 12.67 3.88 3.121.72 3.853.03 LT

5.571.91 6.354.03 241.67 94.96 276.67 79.41 190.00 149.21 249.67 134.97 1095.83 550.64 1277.50 552.24 20.33 11.36 27.33 7.63 21.83 13.18 14.50 7.48 3.121.04 4.855.27 OBLA

8.522.65 10.92 8.63 300.00 111.71 348.33 100.68 551.00 261.30 595.33

356.95 2782.50 553.76 2889.83 928.98 51.33 13.57 61.17 26.48 49.17 38.52 21.17 17.10 6.034.96 6.106.20 OBLA-Peak Exercise intensities

Table 4 Changes in plasma renin activity, hormonal factors relate to vasoconstriction and stroke volume during exercise and recovery.

PRA = plasma Renin activity; PAC = plasma aldosterone concentration; ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide. Ad = adrenaline; Nor = noradrenalin;

DA = dopamine; One of six in insertion homozygous (I/I) and four of six in deletion homozygous (D/D) could perform OBLA-Peak intensity completely. Log translated values were used for 2 way ANOVA repeated measurement. Values are given as mean±SD.

I/I D/D

DP I/I

D/D (beat/min)HR

111.83 22.22 119.83 19.88 15616 168173822 6984 Recovery

0.43 0.53 P-value 98.00

13.73 90.17 11.02 13184 130172132 2599 1/2 LT

128.50 18.61 112.33 12.63 21406 171504308 2484 LT

164.50 20.27 160.83 17.57 30649 294344853 5813 OBLA

191.00 9.23 186.50 389015.32 373352786 6012 OBLA-Peak Exercise intensities

Table 5 Heart rate and double product during execise and recovery.

HR = heart rate; DP = double product. One of six in insertion homozygous (I/I) and four of six in deletion homozygous (D/D) could perform OBLA-Peak intensity completely. Log translated values were used for 2 way ANOVA repeated measurement. Values are given as mean±SD.

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0 50 100 150 200 250 300

7 12 17 22 27 32

ACE (IU/l/37℃)

AngII(pg/ml)

Figure 4 Scatterplot shows relationship between changes in Angiotensin I converting enzyme (ACE) activity and Angiotensin II concentration at rest, during exercise and recovery in subjects with insertion (I/I) (○) and deletion (D/D)(●) homozygous of ACE gene insertion/deletion polymorphism. No correlation was observed in I/I (r=0.31;

N.S.) and D/D (r=0.03; N.S.).

0 50 100 150 200 250 300

0 500 1000 1500 2000 2500

AngI (pg/ml)

AngII(pg/ml)

Figure 5 Scatter plot shows relationship between changes in Angiotensin I (Ang I) and Angiotensin II(Ang II) concentration at rest, during exercise and recovery in subjects with insertion (I/I) (○) and deletion (D/D) (●) homozygous of Angiotensin I converting enzyme gene insertion/deletion polymorphism. Signifi cant correlations were observed in I/I (---; r=0.72; p<0.01) and D/D ( ; r=0.94; p<0.01).

80 100 120 140 160 180 200 220 240

1/2 LT LT OBLA OBLA

-Peak Recovery

SBP(mmHg)

40 50 60 70 80 90 100 110 120

DBP(mmHg)

70 80 90 100 110 120 130 140 150 160

MBP(mmHg)

1/2 LT LT OBLA OBLA

-Peak Recovery

1/2 LT LT OBLA OBLA

-Peak Recovery Figure 3 Changes in systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure during exercise and recovery in insertion (○) and deletion (●) homozygous of Angiotensin I converting enzyme gene insertion/deletion polymorphism.

One of six in insertion homozygous and four of six in deletion homozygous could perform OBLA-Peak intensity completely. Log translated values were used for 2 way ANOVA repeated measure (SBP; p=0.68, DBP; p=0.77, MBP; p=0.76). Data are shown as mean and SD.

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Ang II during exercise changes depending on Ang I.

In conclusion, the results of the present study suggest that ACE gene I/D polymorphism may not infl uence circulatory response during exercise and the change of well-known fl uid factors that control it.

Acknowledgement

This study was supported by Grant in Aid for Scientifi c Research from the Ministry of Education, Culture, Sports, Science and Technology: Base Study B 15300229. We conducted the study as a theme of research corresponding to the needs of citizens of Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology, a project conducted from 1999 to 2004. We wish to express our sincere gratitude here. We are also grateful to the Exercise Physiology Course of Health and Science Graduate School at Fukuoka University for supporting us as our subjects and experimenters.

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Name:

Takuro Tobina Affi liation:

Graduate School of Education, Hokkaido University

(Graduate School of Physical Education, Fukuoka University)

Address:

Nishi 7, Kita 11-jo, Kita-ku, Sapporo City, Hokkaido 060-0811 Japan Brief Biographical History:

2000- Master’s Program. Graduate School of Physical Educatin, Fukuoka University.

2002- Doctoral Program, Graduate School of Education, Hokkaido University.

Membership in Learned Societies:

• The Japanese Society of Physical Fitness and Sports Medicine.

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