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The FASEB Journal article fj.13-245480. Published online January 17, 2014.
The FASEB Journal • Research Communication
Resistance training restores muscle sex steroid
hormone steroidogenesis in older men
Koji Sato, Motoyuki Iemitsu, Kenji Matsutani, Toshiyuki Kurihara, Takafumi Hamaoka,
and Satoshi Fujita
Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan ABSTRACT
Skeletal muscle can synthesize testoster-
cular system, brain, and skeletal muscle (1). As one and 5␣-dihydrotestosterone (DHT) from dehydro-
precursors of sex steroid hormones, dehydroepi- epiandrosterone (DHEA) via steroidogenic enzymes in
vitro, but hormone levels and steroidogenic enzyme
(DHEA-S) play critical physiological roles in main- expression decline with aging. Resistance exercise has
taining steroidogenesis in peripheral tissues (1).
been shown to increase in plasma sex steroid hormone
DHEA is converted to testosterone by 3␤-hydroxys- levels. However, it remains unclear whether resistance
teroid dehydrogenase (HSD) and 17␤-HSD and tes- training can restore impaired steroidogenic enzyme
tosterone then converted to 5␣-dihydrotestosterone expressions in older individuals. Six young and 13
(DHT) by 5␣-reductase (1). Aging leads to reduced older men were recruited, and muscle biopsies were
serum levels of DHEA (2), which are significantly taken from the vastus lateralis at basal state. The same
correlated with increased risks of metabolic syn- group of older subjects underwent resistance training
drome (3). Thus, it seems critical to prevent the involving knee extension and flexion exercises for 12
aging-induced attenuation of steroidogenesis for wk, and post-training biopsies were performed 4 –5 d
after the last exercise session. Muscular sex steroid
In our previous studies, we demonstrated that hormone levels and sex steroidgenesis-related enzyme
skeletal muscle can synthesize testosterone, estradiol, expressions were significantly lower in older subjects
and DHT from DHEA locally in cultured skeletal than younger ones at baseline, but 12 wk of resistance
muscle and rat muscle tissue models (4, 5). In a training significantly restored hormone levels (DHEA:
recent study by Vingren et al. (6), it was found that 432؎26 at baseline, 682؎31 pg/␮g protein, DHT:
acute resistance exercise for young human subjects 6.2؎0.9 at baseline, 9.8؎1.4 pg/␮g protein). Further-
did not change muscular steroidogenesis-related en- more, the steroidogenesis-related enzymes such as 3␤-
zymes. Moreover, another study reported that gene hydroxysteroid dehydrogenase (HSD), 17␤-HSD, and
expression of steroidogenic enzymes were detected 5␣-reductase expressions were significantly restored by
in female subjects, and they declined with aging, resistance training. We conclude progressive resis-
specifically 3␤-HSD and P450 aromatase (2). In ad- tance training restores age-related declines in sex
dition, a significant correlation was found between steroidogenic enzyme and muscle sex steroid hor-
serum DHEA level and muscle force per cross-sec- mone levels in older men.—Sato, K., Iemitsu, M.,
tional area (CSA; ref. 2). However, the effect of aging Matsutani, K., Kurihara, T., Hamaoka, T., Fujita, S.
on steroidogenic enzymes and muscular sex steroid Resistance training restores muscle sex steroid hor-
hormone levels in men has not been investigated. If mone steroidogenesis in older men. FASEB J. 28,
it is possible to improve the aging-induced decrease 000 – 000 (2014). www.fasebj.org
in muscular steroidogenesis, this improvement maycontribute to augmentation of muscle mass. Exercise, Key Words: skeletal muscle ⅐ exercise ⅐ aging ⅐ muscle strength especially resistance exercise, is characterized bycontracting skeletal muscles and has been shown toincrease plasma DHT levels in the older adults (7).
Steroid sex hormones, which are secreted mainly The program of chronic resistance exercise com- by the ovary, testis, and adrenal cortex, regulate bined with endurance trainings elevated serum levels diverse physiological processes in target tissues, in- of testosterone and estradiol, whereas resistance cluding reproductive organs, bone, liver, cardiovas- training itself only increased serum DHT level ac-cording to the previous study (8). Thus, resistanceexercise may reverse aging-induced impairment of Abbreviations: CSA, cross-sectional area; DHEA, dehydro- epiandrosterone; DHT, 5␣-dihydrotestosterone; HRP, horse- radish peroxidase; HSD, hydroxysteroid dehydrogenase; Correspondence: Ritsumeikan University, 1-1-1 Nojihigashi, IGF-1: insulin-like growth factor 1; MRI, magnetic resonance Kusatsu, Shiga, Japan. 525-8577. E-mail: safujita@fc.ritsumei.
imaging; mTOR, mammalian target of rapamycin; 1-RM, 1-repetition maximum; RPE, rating of perceived exertion steroidogenesis in skeletal muscle with concomitant of 1-RM was repeated every 4 wk to adjust the training weights increase in muscle mass and function in older indi- viduals. However, it remains unclear whether chronicresistance exercise induces changes in muscle sex Magnetic resonance imaging (MRI)
Therefore the aim of this study was to investigate MRI was used to determine the muscle CSA of the quadri-ceps. A 1.5-T magnetic resonance system (Signa HDxt; GE whether 12 wk of progressive resistance training can Medical Systems) was used to obtain a series of axial slices enhance muscle steroidogenesis and muscle sex steroid from the superior border of the patella to the anterior hormones in older men. To achieve this, we measured superior iliac spine, encompassing the entire quadriceps seroidogenic enzymes such as 3␤-HSD, 17␤-HSD, and femoris muscle group. The images were obtained from 10- 5␣-reductase protein expressions, as well as muscular mm-thick slices. Multislice T1-weighed spin-echo images were sex steroid hormone levels especially, DHEA, free- acquired to guide the positioning of the volume of interest testosterone, and DHT levels, which were measured and used for measuring muscle CSA at the level of themidthigh (9). Subjects were instructed not to drink or eat before and after resistance training in older subjects.
after midnight on the night before the scans, which were We hypothesized that 12 wk resistance training en- hanced impaired muscular steroidogenesis in oldermen.
Muscle biopsies
Muscle biopsies were obtained from the lateral portion of the MATERIALS AND METHODS
vastus lateralis using a Core biopsy instrument (Bard Max-Core; Bard Peripheral Vascular, Tempe, AZ, USA) understerile conditions with local anesthesia (1% lidocaine). The Subjects
subjects were fed the same standard dinner (1800 kcal) at1800 h and were allowed only water ad libitum after 2200 h. All Thirteen older men (mean age: 67.2Ϯ1.8 yr) and 6 young subjects participated in an overnight fast under basal condi- men (mean age, 24.3Ϯ1.3 yr) volunteered to participate in tions and refrained from exercise for 24 h before study this study. All volunteers provided written informed consent participation. The biopsy for older subjects after 12 wk of before participating in the study, which was approved by the resistance training was performed 4 –5 d after the last exercise Ethics Committee of Ritsumeikan University and was con- session to minimize its acute effects. The muscle sample was ducted in accordance with the Declaration of Helsinki. The quickly rinsed with ice-cold saline, blotted, and then frozen older subjects were examined by a physician to confirm that immediately in liquid nitrogen and stored at Ϫ80°C until none had medical problems that might preclude participa- tion or affect the results. None of the subjects regularlyperformed resistance exercise, but they were moderately Immunoblot analysis
active. Their physical activities included walking and jogging.
Subjects were instructed to continue their normal activities of Muscle specimens were homogenized with 20 mM Tris-HCl, daily living and usual diets throughout the experimental pH 7.8; 300 mM NaCl; 2 mM ethylenediaminetetraacetic acid; 2 mM dithiothreitol; 2% nonidet P-40 (Nonidet P-40); 0.2% One-repetition maximum (1-RM) strength tests were per- sodium lauryl sulfate; 0.2% sodium deoxycholate; 0.5 mM formed every 4 wk to adjust training intensity. Isokinetic peak phenylmethylsulfonyl fluoride; 60 ␮g/ml aprotinin; and 1 torque was assessed in the knee extensors before and after ␮g/ml leupeptin. The homogenate was gently mixed for 30 training using a dynamometer (Biodex System 4; Biodex min at 4°C and then centrifuged at 12,000 g for 15 min at 4°C.
Medical Systems, Shirley, NY, USA). To avoid a possible The protein concentration of the resulting supernatant was learning effect, a 1-RM test was performed twice at least 3 d determined. Samples (40 ␮g protein) were denatured at 96°C after the first 1-RM measurement. The same investigator for 7 min in Laemmli buffer. Western blot analysis was measured 1-RM strength before and after training using the performed essentially as described previously (11). Briefly, same levels of vocal encouragement. In addition, body com- muscle samples were separated using 10% SDS-polyacryl- position and lean mass were measured by dual-energy X-ray amide gels and transferred to polyvinylidene difluoride absorptiometry (Lunar Prodigy, GE Medical Systems, Little (PVDF) membranes (Millipore, Billerica, MA, USA). The membranes were then treated for 24 h at 4°C with blockingbuffer (5% skim milk in phosphate-buffered saline with 0.1% Resistance training
Tween 20). Next, the membranes were probed with antibod-ies against 17␤-HSD, 3␤-HSD, and the androgen receptor Resistance exercise sessions for older subjects were carried (Cell Signaling Technology, Beverly, MA, USA), all diluted out 3ϫ/wk on alternate days for 12 wk. Experienced trainers 1:1000 with blocking buffer. Anti-5␣-reductase (Abnova, Tai- supervised all training sessions to ensure that proper tech- pei, Taiwan) was used at 1:500 dilution. The membranes were nique and progression were being used in each exercise washed 3 times with PBS-T and then incubated for 1 h at session. Each exercise included 2 exercises; bilateral knee room temperature with a horseradish peroxidase (HRP)- extension involving the leg extensors, and bilateral knee conjugated secondary antibody and anti-rabbit immunoglob- flexion exercising the leg flexors. The starting weight used ulin (Cell Signaling Technology), diluted 1:3000 in blocking during the resistance exercise portion of this study was 70% of buffer. Next, the membranes were washed 3 times with PBS-T.
each subject’s predetermined 1-RM for 3 sets of 10 repetitions Finally, 17␤-HSD, 3␤-HSD, 5␣-reductase, and androgen re- using weight-stack machines (Life Fitness, Tokyo, Japan). The ceptor proteins were detected using an enhanced chemilumi- rest period between sets was 3 min. The weight was increased nescence plus system (GE Healthcare Biosciences, Piscataway, for each subject when his rating of perceived exertion (RPE) NJ, USA) and visualized using an LAS4000 imager (GE was Ͻ16 for the 10th repetition of the 3rd set. Determination of resistance exercise induced significant increases inmaximal isokinetic extension strength and quadriceps Serum hormone levels
Serum sex steroid hormone and IGF-1 levels were significantly lower in older compared with young subjects at baseline. Resistance exercise was associ- ated with increased serum DHEA and DHT levels (PϽ0.01). Although there was no statistically signifi- cant change in either serum free testosterone (Pϭ0.052) or IGF-1 (Pϭ0.055) concentrations, there was a tendency toward increased serum levels with
resistance exercise (Table 2).
Young pre, young subjects at baseline; old pre, older subjects at baseline; old post, older subjects after training. Values are means ϮSE. *P Ͻ 0.01 vs. old pre.
Muscle sex steroid hormone levels
DHEA and DHT levels in skeletal muscle were signifi- Sandwich enzyme immunoassay (EIA)
cantly lower in older as compared with young subjectsat baseline. However, DHEA levels increased signifi- Muscle sample was homogenized in same method withimmunoblot analysis. For the determination of DHEA, free cantly in the older subjects after the training period testosterone, DHT, and insulin-like growth factor 1 (IGF-1) (PϽ0.01). Baseline muscle free testosterone levels were levels, muscle samples were diluted by 200 times with each also significantly lower in the older subjects than the assay buffer (11). All techniques and materials used in young subjects, but free testosterone levels increased these analyses were in accordance with the manufacturer’s significantly after training. Moreover, muscle DHT lev- protocol. The levels of DHEA (Assay Designs, Ann Arbor, els were lower in older compared with young subjects.
MI, USA), free testosterone (Cayman Chemical, Ann Ar-bor, MI, USA), DHT (Assay Designs), and IGF-1 (R&D In contrast, 12 wk of training were associated with Systems, Minneapolis, MN, USA) in plasma and skeletal significant increases in muscle DHT levels in older muscle extracts were determined using a sandwich-enzyme subjects. Resistance training restored muscular sex ste- immunoassay kit. The immobilized polyclonal antibodies roid hormones in older subjects to levels seen in the were raised against DHEA, free testosterone, DHT, and young subjects (Fig. 1).
IGF-1, whereas the secondary HRP-coupled antibodieswere monoclonal. Optical density at 450 nm was qualifiedusing a microplate reader (BioLumin 960; Molecular Dy- Sex steroidogenic enzyme expression in muscle
namics, Tokyo, Japan). All samples were assayed in dupli-cate. The average coefficient of variation between dupli- Expression of steroidogenic enzymes such as 3␤-HSD and 17␤-HSD were significantly lower in older sub-jects before training. However, resistance training Statistical analysis
was associated with significant increases in the ex-
pression of steroidogenic enzymes (PϽ0.01; Fig. 2).
All values are means Ϯ se, unless indicated otherwise. Statis- 5␣-Reductase and androgen receptor expression was tical analysis was performed using 1-way ANOVA. A post hoc also higher after 12 wk of resistance training in older Bonferroni test was used to correct for multiple comparisons when analyses revealed significant differences. For ANOVA, PϽ0.01; Fig. 3). In addition, significant
P Ͻ 0.05 was considered to be significant; P Ͻ 0.01 was correlation was seen between percentage change of considered to be significant for post hoc tests. Relationships muscular DHEA and DHT levels (rϭ0.721, PϽ0.001).
between the differences in serum or muscle sex steroid Furthermore, 5␣-reductase protein expression was hormone concentrations and muscle power and quadricepsCSA, respectively, were determined using Pearson correlationcoefficients.
TABLE 2. Serum hormone concentrations At baseline, older and young subjects had similar body weight, although older subjects had a significantly higher percentage of body fat. Maximal isokinetic extension strength was significantly lower in older subjects. Furthermore, older subjects had lower quad- Young pre, young subjects at baseline; old pre, older subjects at riceps CSA than young subjects at baseline and after baseline; old post, older subjects after training. Values are means Ϯ resistance exercise training (Table 1). However, 12 wk
SE. *P Ͻ 0.01 vs. old pre.
EXERCISE TRAINING AND STEROIDOGENESIS IN HUMAN MUSCLE Figure 1. Effect of 12 wk of resistance exercise on DHEA, free testosterone, and DHT levels in muscle. Muscle concentrations
of DHEA (A), free testosterone (B), and DHT (C) in both young and older subjects were normalized based on total protein
levels. Young pre, young subjects at baseline; old pre, older subjects at baseline; old post, older subjects after training. Data
represent means Ϯ se. *P Ͻ 0.01 vs. old pre.
significantly correlated with muscular DHT level protein expression was significantly correlated with both isokinetic strength (PϽ0.001) and CSA (PϽ0.001).
Relationship between sex steroid hormone
concentrations and muscle strength
and mass
DISCUSSION
No significant correlations were found between per-centage changes in serum hormone concentrations Here we report for the first time that 12 wk progres- and isokinetic strength or between percentage sive resistance training appeared to increase or par- changes in serum hormone concentrations and mus- tially reverse the age-associated reduction in muscle cle CSA (PϾ0.1). However, the percentage change of sex steroid hormone levels and muscular steroido- intramuscular DHEA and free testosterone levels was genic enzyme protein expression in men. Although significantly correlated with isokinetic strength.
protein expression of steroidogenic enzymes such as Moreover, muscular DHT levels were significantly 3␤-HSD, 17␤-HSD, 5␣-reductase, and androgen re- correlated with both muscle power (PϽ0.001) and ceptor protein expressions in muscle were signifi- CSA (Pϭ0.018; Table 3). In addition, 5␣-reductase
cantly lower in older men compared with younger Figure 2. Effect of exercise on HSD and 17␤-HSD protein expression. Representative immunoblotting results and histograms
of 3␤-HSD (A) and 17␤-HSD (B) protein expression are shown. Young pre, young subjects at baseline; old pre, older subjects
at baseline; old post, older subjects after training; AU, arbitrary unit. Data represent means Ϯ se. *P Ͻ 0.01 vs. old pre.
Figure 3. Effect of exercise on 5␣-reductase type 1 and androgen receptor protein expression. A) Representative immunoblot-
ting results and histogram of 5␣-reductase type 1 protein expression in the muscle. B) Representative immunoblotting results
and histograms of androgen receptor protein expression. Young pre, young subjects at baseline; old pre, older subjects at
baseline; old post, older subjects after training. Data represent means Ϯ se. *P Ͻ 0.01 vs. old pre.
counterparts at baseline, 12 wk of resistance training 15) and accelerated sarcopenia (15, 16). Using in significantly increased levels of these enzymes and vitro and in vivo animal models, we have previously restored both serum and muscle levels of DHEA, free demonstrated that testosterone and DHT can be testosterone, and DHT to levels seen in young sub- synthesized from DHEA in muscle (4, 5) and acute jects. Interestingly muscular steroid hormone levels and chronic aerobic exercise increases sex steroid significantly correlated with muscle strength and hormones in muscle with concomitant elevations of CSA. Thus, progressive resistance training seems to serum steroid hormones in rats (11, 17). Further- restore muscle sex steroid hormone levels via en- more, exercise, especially resistance exercise, is char- hancement of steroidogenesis-related enzyme ex- acterized by contracting skeletal muscles and in- pressions in the skeletal muscle and may partly creased sex steroid hormone levels in the older contribute to the increase in muscle strength and adults (7). In the present human study, the serum and muscle levels of sex steroid hormones were Aging is associated with decreases in serum DHEA significantly lower in older as compared with younger levels (12). Consequently, reductions in sex steroid men However, resistance training restored both hormone concentrations in blood would result in an plasma and muscular sex steroid hormone levels in increased risk of the metabolic syndrome (3, 13, 14, older subjects. Importantly, restoring DHT has amore potent effect on target tissue than DHEA and TABLE 3. Association of systemic and local hormone levels with testosterone because of its greater affinity to the muscle power and CSA in percentage changes androgen receptor (1). Therefore, resistance train-ing-induced increases in muscular DHT and andro- gen receptor expressions may have contributed to the training effect in older subjects.
A previous study reported gene expression of steroido- genic enzymes declines with aging, especially 3␤-HSD and P450 aromatase in women (2). In the present study, steroidogenic enzyme expressions such as 3␤-HSD, 17␤- HSD, and 5␣-reductase significantly were lower in older men compared with young at baseline. However, 12 wk resistance training significantly increased muscular ste- roidogenic enzyme expressions; therefore, the training- induced restoration of impaired muscular steroidogenic enzymes in older men may have increased the synthesis Italics denote significance at P Ͻ 0.05.
and intramuscular levels of sex steroid hormones.
EXERCISE TRAINING AND STEROIDOGENESIS IN HUMAN MUSCLE In the previous study, chronic resistance training lower in older men as compared with young men.
induced to elevate serum testosterone and DHEA levels However, progressive resistance training significantly (8). A recent study reported that gene expression of restored age-related decline of steroidogenic enzyme steroidogenesis-related enzymes in human muscle re- expressions and sex steroid hormone levels, and duced with aging (2). In addition, serum DHEA-S level these enzymes and hormone levels significantly cor- was significantly correlated with muscle force per CSA related with muscle size and strength. Therefore, in female subjects (2). In the present study, significant resistance training-induced increase muscular sex correlations were seen between training effects of mus- steroid hormone may positively affect age-related cle sex steroid hormone levels, muscle CSA and maxi- concerns such as accidental falls, diabetes, sarcope- mum isokinetic strength. In addition, steroidogenic nia, and osteoporosis and may improve the quality of enzyme especially 5␣-reductase protein expression sig- nificantly correlated with muscle CSA and isokineticstrength. However, no significant correlation was seen The authors specially thank Dr. Noboru Mesaki for sup- between serum DHEA level and muscle force per CSA porting this study. This work was supported by grants-in-aidfor scientific research from the Ministry of Education, Cul- in men (rϭ0.318, Pϭ0.082). The mechanism underly- ture, Sports, Science, and Technology of Japan (23700849, ing the relationship between androgen levels in muscle 24300235, and 22680050). This work was also funded by the and muscle mass and strength remains to be eluci- Yamaha Motor Foundation for Sports (to K.S., S.F., and M.I.).
dated. In several previous studies, androgen replace- The authors declare no conflicts of interest.
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