Vol. 88, Issue 4, 1271-1276, April 2000
Interaction of the effects between vitamin D receptor
polymorphism and exercise training on bone metabolism
Orie
Tajima1,
Noriko
Ashizawa2,
Tomoo
Ishii3,
Hitoshi
Amagai4,
Tomoko
Mashimo1,
Li Jing
Liu1,
Shinichi
Saitoh1,
Kumpei
Tokuyama1, and
Masashige
Suzuki1
1 Institute of Health and Sport Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8574;
2 National Cancer Center, Tokyo 104-0043;
3 Institute of Clinical Medical Science,
University of Tsukuba, Tsukuba, Ibaraki 305-0006; and
4 Tsukuba College of Medical Technology and
Nursing, Tsukuba, Ibaraki 305-0006, Japan
 |
ABSTRACT |
Bone metabolism is strongly
influenced by heredity and environmental factors. To investigate
interaction of the effects between vitamin D receptor polymorphism by
Fok I and resistance exercise training on bone metabolism,
young male subjects with FF genotype (F, n = 10) and Ff or ff
genotypes (f, n = 10) followed 1 mo of weight training, and
changes in bone metabolism were compared. An additional 14 subjects served as a sedentary control. Biomarkers of bone formation,
bone-specific alkaline phosphatase, and osteocalcin were significantly
increased by training in both F and f groups. 1,25-Dihydroxyvitamin
D3, known to upregulate bone formation, was also increased
by the training in the f but not in the F group. Bone resorption
assessed by cross-linked NH2-terminal teropeptide of type I
collagen was significantly suppressed by the training, and the decrease
in F was greater and longer lasting than that in f group. In
conclusion, stimulation of bone formation and suppression of bone
resorption occurred within 1 mo in young men. Despite a significant
increase in 1,25-dihydroxyvitamin D3 in the f group but not
in the F group, the response of bone metabolism to the training in the
F was similar to or greater than that in f group, suggesting a
functional difference between vitamin D receptor genotypes f and F.
Fok I; bone formation; bone resorption
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INTRODUCTION |
BONE MINERAL DENSITY (BMD) is influenced by environment
(35) and heredity (28, 31). Mechanical load is one of the major environmental factors to influence BMD and bone metabolism (12). We
have shown that resistance exercise training for 4 mo increased bone
formation, whereas it transiently suppressed bone resorption, and such
adaptive changes of bone metabolism to the training occurred during the
early period of the training in young men (13).
BMD and bone turnover in adults are under genetic influence; in
particular, serum osteocalcin concentration is strongly correlated in
monozygotic twin pairs (19). The vitamin D receptor (VDR) is a good
genetic candidate for a prime regulator of BMD and bone metabolism (8)
because of its acting to mediate the vitamin D endocrine system through
binding of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and subsequently
controlling the transcription of target genes relating to calcium
homeostasis (32). Common allelic variants in the VDR gene have been
associated with BMD (24). The VDR gene has two potential translation
initiation sites (ATG), and a thymine/cytosine polymorphism has been
noted in the first ATG. This polymorphism was first found in the
patients with vitamin D-dependent rickets type II (30). Recent studies
have reported that the polymorphism at the translation initiation site
of the VDR gene correlates significantly with BMD or with a rate of
bone loss in the healthy population, whereas some have not observed these associations (1, 2, 7, 10, 11, 14, 15, 18, 23).
Although the effects of mechanical load and genetic factors on bone
metabolism have been intensively studied, there is a paucity of
literature relating these two factors (27). As the first attempt in
human study, we recruited young men with different VDR genotypes and
compared the response of biomarkers of bone metabolism between the two
training groups during the first month of resistance exercise training.
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MATERIALS AND METHODS |
Subjects.
Allele frequencies for the VDR polymorphism at the translation
initiation site were determined among 81 unrelated Japanese young adult
male volunteers (18-31 yr) who had not participated in a regular
exercise program for at least 1 year. The response of bone metabolism
to resistance exercise training between groups with different VDR
genotypes was investigated in 34 normal, healthy randomly selected male
volunteers (22-26 yr) who were taking no medications that would
alter calcium or bone homeostasis. Ten men previously identified to
have the FF genotype were selected as the F-group training subjects,
and another 10 men with f allele, including 7 ff and 3 Ff, were
selected as the f-group training subjects. An additional fourteen
subjects (8 FF and 6 Ff) were selected as the sedentary control. There
were no significant differences in physical characteristics among these
groups (Table 1).
VDR genotype.
VDR gene polymorphism at the translation initiation site was determined
by a restriction fragment length polymorphism by using the restriction
endonuclease Fok I.
DNA was extracted from whole blood by using the sodium iodide method
(DNA extractor WB kit, Wako Pure Chemical Industries, Osaka, Japan) and
was amplified by the PCR method (2). PCR products were digested with
Fok I and then electrophoresed through a 2% agarose gel
containing ethidium bromide. VDR alleles containing the Fok I
site were denoted by f and alleles lacking the site were denoted by F,
and individuals were scored as FF homozygotes, Ff heterozygotes, or ff
homozygotes according to the digestion pattern (15).
Training program.
The two training groups followed a weight training program consisting
of eight exercises (3, 13). The training was performed 12 times at 3 times per week for 1 mo. During the first half of the training period,
training subjects performed two sets of 10 repetitions of each exercise
[60% of one repetition maximum (1RM) for the first set and 75%
of 1RM for the second set, respectively]. During the latter half
of the training period, training subjects performed three sets of
exercise to further load the skeleton (60% of 1RM for the first set,
75% of 1RM for the second and third sets, respectively). All exercises
were performed on a weight machine (Uesaka). Weights were increased on
an individual basis as strength improved. Improved strength was
measured by a 1RM test and adjusted to accommodate strength gains for
each individual after six training periods.
Diet.
Each subject was given a daily supplement of 600 mg of calcium (Ozka)
to ensure an adequate calcium intake of more than 800 mg/day during the
1-mo experimental period. Control diets containing 2,421 ± 86 kcal
(58.3 ± 1.9% carbohydrate, 13.2 ± 0.6% protein, and 28.5 ± 2.0% fat) and 902 ± 35 mg of calcium were given for 3 days, after
which blood and urine samples were collected.
Biochemical analysis.
To evaluate the effects of the resistance exercise training, biomarkers
of bone metabolism were measured before and after the training period
on resting days in all groups. Additionally, the biomarkers in the
training groups were assessed at three points after exercise days
during the training period. Fasting blood and 24-h urine samples were
stored at 
60°C to be run simultaneously at the conclusion of
the study to eliminate interassay variations.
As bone formation markers, serum bone-specific alkaline phosphatase
(B-ALP) activity was measured by an ELISA (Alkphase-B, Metra
Biosystems, Palo Alto, CA), and serum osteocalcin was determined by
specific two-site RIA for human osteocalcin (ELSA-OSTEO, CIS BioInternational, Bagnols, France). As bone resorption markers, urinary
deoxypyridinoline (DPYR) was measured by an ELISA (Pyrilinks-D, Metra
Biosystems), and urinary cross-linked NH2-terminal
teropeptide of type I collagen (NTx) was measured by an ELISA
(Osteomark, Ostex International, Seattle, WA). In addition,
1,25(OH)2D3, the active hormonal form, was
measured by radio receptor assay
[1,25(OH)2D3 kit (SRL), Yamasa, Chiba,
Japan]. Duplicate measurements were made of all samples.
Data analysis.
Values are means ± SE, and Mann-Whitney's U tests were used
to compare differences in BMD and biochemical measurements between F-
and f-group subjects before the training intervention.
The response of each biochemical measurement to resistance exercise was
expressed as the percentage change from the baseline value, and the
data are means ± SE. To determine the effect of training for 1 mo,
paired Wilcoxon's tests were used. Multifactor analysis of variance
(MANOVA) with Fisher's post hoc test was used to evaluate the
interaction of effect to bone metabolism between exercise training and
VDR genotype. Statistical significance was taken at the P < 0.05 level.
| |
RESULTS |
VDR polymorphism.
The frequency of VDR genotypes by Fok I in this study was
50.6% (n = 41) FF, 40.7% (n = 33) Ff, and 8.7%
(n = 7) ff. There were no statistically significant differences
between the two groups of VDR genotype by Fok I, FF and one or
more f allele (Ff or ff), in physical characteristics of the subjects
(Table 2).
Effects of resistance exercise training.
In evaluating the effects of the resistance exercise training, all of
the bone metabolism markers except urinary DPYR excretion in trained
subjects were significantly changed after the training period compared
with baseline values (Table 3).
Additionally, serum concentration of
1,25(OH)2D3 seemed to be increased after the
training period in the trained subjects, but the difference was not
statistically significant (P = 0.10). There were no significant changes in any biochemical measurements in sedentary group subjects after the experimental period.
Gene-environment interaction.
When the two training groups were separately analyzed, similar changes
in the bone metabolism markers in each group were observed, but the
increase in serum B-ALP activity in the f group was not statistically
significant (P = 0.14). Interestingly, the response of
circulating 1,25(OH)2D3 to exercise training
depends on VDR genotypes, and an increase in
1,25(OH)2D3 after 1 mo training was observed in
the f but not in the F group (Fig.
1). Furthermore, gene-environment interaction in 1,25(OH)2D3
as evaluated by MANOVA was statistically significant (P < 0.05).
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Fig. 1.
Effects of resistance exercise training on biochemical measurements in
training groups F (FF genotype; solid bars) and f (Ff or ff genotype;
open bars). Each value is expressed as percent change (%change) from
baseline value, and data are means ± SE. *,** Significant
difference from baseline value of each group (*P < 0.05, **P < 0.01); # significant difference between F and f
groups (P < 0.05). Gene-environment interaction on
circulating 1,25-dihydroxyvitamin D3
[1,25(OH)2D3] as evaluated by
multifactor analysis of variance (MANOVA) was statistically significant
(P < 0.05) but not on bone-specific alkaline phosphatase
(B-ALP), osteocalcin, and cross-linked NH2-terminal
teropeptide of type I collagen (NTx) (P = 0.44, P = 0.51, and P = 0.63, respectively).
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During the exercise training period, the time course of changes in
biomarkers of bone metabolism and circulating
1,25(OH)2D3 was compared between the F and f
groups (Figs.
2-5).
Serum B-ALP activity and serum osteocalcin concentration were similarly
increased in both training groups during the training period.
1,25(OH)2D3 was significantly increased during
the latter half of the training period in type f but not in type F. Urinary NTx excretion was significantly decreased by the training in
both type F and type f during the early period of the training but that
in type f seemed to gradually return to its baseline value.
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Fig. 2.
Time course of serum B-ALP activity in training groups F and f. Values
are expressed as %change from baseline value; data are means ± SE.
** Significant increase from baseline value of each group (P < 0.01). Gene-environment interaction on %change of B-ALP was
evaluated by MANOVA (P = 0.99).
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Fig. 3.
Time course of serum osteocalcin concentration in training groups F and
f. Values are expressed as %change from baseline value; data are means ± SE. *,** Significant increase from baseline value of each group
(*P < 0.05, **P < 0.01). Gene-environment
interaction on %change of osteocalcin was evaluated by MANOVA
(P = 0.95).
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Fig. 4.
Time course of serum concentration of
1,25(OH)2D3 in training groups F and f. Values
are expressed as %change from baseline value; data are means ± SE.
* Significant increase from baseline value of each group (P < 0.05); ## significant difference between F and f groups
(P < 0.01). Gene-environment interaction on %change of
1,25(OH)2D3 was evaluated by MANOVA (P = 0.08).
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Fig. 5.
Time course of urinary excretion of NTx in training groups F and f.
Values are expressed as %change from baseline value; data are means ± SE. *,** Significant decrease from baseline value of each group
(*P < 0.05, **P < 0.01); # significant
difference between F and f groups (P < 0.05).
Gene-environment interaction on %change of NTx was evaluated by MANOVA
(P = 0.23).
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| |
DISCUSSION |
The coupling of bone resorption and formation plays an important role
for the maintenance of the adult skeleton (29). Many investigators have
suggested that exercise affects BMD (4, 6, 20, 21) and changes bone
metabolism (3, 5, 9, 22, 26, 33). In our present study, resistance
exercise training enhanced bone formation and suppressed bone
resorption markers, concordant with our previous study in young men
(13). When data from all the trained subjects were combined, the
changes in bone formation assessed by serum osteocalcin concentration
and B-ALP activity were significantly increased. Concerning response of bone resorption to the exercise, urinary NTx excretion was
significantly decreased by the training but urinary excretion of DPYR
did not decrease. This difference in changes in the two biomarkers of bone resorption was similar to the report that the significant decrease
of urinary excretion of NTx was observed by 5-wk endurance training in adolescent male subjects but that of DPYR did not significantly change (9). Moreover, it was reported that changes in
urinary NTx excretion were greater than those of DPYR in bisphosphonate treatment of hypercalcemia (34), suggesting that NTx may be a more
sensitive indicator of bone resorption than is DPYR. It is suggested
that stimulation of bone formation and suppression of bone resorption,
taken together, began within the first month of resistance training in
young men.
To investigate the interaction between the effect of genetic
factor and exercise on bone metabolism, response of bone metabolism to
resistance training was compared in groups F and f. Screening 81 young
men revealed a distribution of VDR genotypes similar to that reported
for middle-aged Japanese women (2, 23), and the subjects with VDR
genotype ff were rare. Low statistical power of the present study
because of a limited number of subjects prevented reaching a clear
conclusion, but our results obtained during the first month of the
training suggest that markers of bone metabolism except urinary NTx
excretion in both groups responded similarly to the training. The
decrease of urinary NTx excretion seems to be greater and longer
lasting in type F than that in type f. Thus resistance exercise
training seems to be more effective in the group of VDR type FF for
suppression of bone resorption than in the group of f, but the
molecular mechanism by which the difference in VDR genotypes affects
NTx excretion remains to be determined.
1,25(OH)2D3 is known to upregulate
B-ALP and osteocalcin in these mRNA levels (17), and especially the
gene expression of the latter is stimulated by
1,25(OH)2D3 through a vitamin D-responsive element in the promoter region of its gene (25). A previous study (5)
has reported that serum concentration of
1,25(OH)2D3 was significantly higher in
muscle-building exercisers than in the sedentary controls. Our present
data suggest an increase in serum 1,25(OH)2D3
concentration by training, but the change was not statistically
significant (P = 0.10). When the two training groups were
analyzed separately, however, serum 1,25(OH)2D3
concentration was increased by training in the f but not in the F
group. Thus response of circulating 1,25(OH)2D3
to resistance training is smaller in the F than in the f group. A
similar response of bone formation to training was observed, suggesting
higher sensitivity of F than f VDR. The polymorphism, detected with
Fok I, at the translation initiation site of the VDR gene
results in a structural change that could potentially alter the
function of the VDR protein. It was reported that the longer allele of
the VDR, designated f, may be less efficient in vitamin D-mediated
transactivation in a transfected cell system (2, 23), although the
significant differences in receptor function including ligand affinity
of each genotype receptor have not been detected (16, 23). The physiological mechanism by which exercise training reveals functional difference in the two VDR isoforms remains to be clarified.
In conclusion, suppression of bone resorption begins during the early
period of resistance training and is followed by stimulation of bone
formation in young Japanese men. Despite a significant increase in
1,25(OH)2D3 in the f group but not in the F
group, the response of bone metabolism to the training in the F group was similar to or greater than that in the f group, suggesting a
functional difference between vitamin D-receptor genotypes f and F.
| |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: K. Tokuyama,
Lab. of Biochemistry of Exercise and Nutrition, Inst. of Health and
Sport Sciences, Univ. of Tsukuba, Tsukuba 305-8574, Japan (E-mail:
tokuyama{at}taiiku.tsukuba.ac.jp).
Received 21 December 1998; accepted in final form 6 December 1999.
| |
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J APPL PHYSIOL 88(4):1271-1276
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Copyright © 2000 the American Physiological Society
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ABSTRACT
INTRODUCTION
