J. Anim Sci. 2008. 86:3418-3423. doi:10.2527/jas.2008-1085
© 2008 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Effects of implants of trenbolone acetate, estradiol, or both, on muscle insulin-like growth factor-I, insulin-like growth factor-I receptor, estrogen receptor-
, and androgen receptor messenger ribonucleic acid levels in feedlot steers1
M. S. Pampusch*,
M. E. White*,
M. R. Hathaway*,
T. J. Baxa
,
K. Y. Chung,
S. L. Parr,
B. J. Johnson,
W. J. Weber* and
W. R. Dayton*,2
* Animal Growth and Development Laboratory, Department of Animal Science, University of Minnesota, 348 ABLMS, Eckles Avenue, St. Paul 55108; and
Department of Animal Sciences and Industry, Kansas State University, Manhattan, KS 66506
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Abstract
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We previously showed that a combined trenbolone acetate (TBA)/estradiol-17β (E2) implant significantly increases IGF-I mRNA levels in the LM of feedlot steers by 28 d after implantation. Here we compare the effects of E2 (25.7 mg), TBA (120 mg), and combined TBA (120 mg)/E2 (24 mg) implants on IGF-I, IGF-I receptor (IGFR-1), estrogen receptor (ER)-
and androgen receptor (AR) mRNA levels in the LM of steers. Twenty yearling crossbred steers with an average initial BW of 421.1 ± 3.6 kg were stratified by BW and randomly assigned to 1 of 4 treatments: 1) nonimplanted, control; 2) implanted with TBA and E2; 3) implanted with E2; or 4) implanted with TBA. Steers were weighed weekly starting on d 0, and muscle biopsy samples were taken from each steer on d 0 (before implantation), 7, 14, and 28. Ribonucleic acid was prepared from each sample and real-time reverse transcription-PCR was used to determine the levels of IGF-I, IGFR-1, ER-, and AR mRNA. Body weight of implanted steers, adjusted by using d-0 BW as a covariant, tended (P = 0.09) to be greater than that of control steers. On d 7 and 28, IGF-I mRNA levels were greater (58 and 78%, respectively; P < 0.009) in E2-implanted animals than in control steers. Similarly, on d 28 the LM IGF-I mRNA level was 65% greater (P = 0.017) in TBA/E2-implanted steers than in control animals. In contrast, the TBA implant did not increase (P = 0.99) LM IGF-I mRNA levels after 28 d of implantation. Muscle IGFR-1, AR, and ER- mRNA levels were not different (P > 0.47) in any of the treated groups compared with the control group. These data suggest that E2 is responsible for the increased muscle IGF-I mRNA level observed in steers implanted with a combined TBA/E2 implant.
Key Words: bovine • estradiol-17β • insulin-like growth factor-I • muscle • trenbolone acetate
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INTRODUCTION
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It is well established that both androgenic and estrogenic steroids significantly enhance feed efficiency, rate of gain, and muscle growth of feedlot cattle; consequently, anabolic steroid implants have been widely used as growth promoters for several decades. Yearling steers implanted for 28 d with trenbolone acetate (TBA) plus estradiol-17β (E2) show an increased rate of gain, feed efficiency, and muscle mass compared with nonimplanted steers (Johnson et al., 1996a
) or steers implanted with TBA or E2 alone (Hancock et al., 1991; Hayden et al., 1993; Johnson et al., 1996a). Steers implanted with TBA/E2 have a greater number of satellite cells in their semimembranosus muscles (Johnson et al., 1998), increased circulating IGF-I concentrations (Johnson et al., 1996b), and increased muscle IGF-I mRNA levels (Pampusch et al., 2003) compared with nonimplanted steers. Additionally, both E2 and TBA increase 3H-thymidine incorporation and IGF-I mRNA expression in bovine satellite cell cultures (Kamanga-Sollo et al., 2004). However, we do not know whether the increase in muscle IGF-I mRNA level observed in TBA/E2-implanted steers is the result of the actions of E2, TBA, or both on muscle tissue. Consequently, we assessed the effects of 28 d of implantation with E2, TBA, or TBA/E2 implants on IGF-I, IGF-I receptor (IGFR-1), estrogen receptor (ER)-, and androgen receptor (AR) mRNA levels in the LM of yearling steers.
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MATERIALS AND METHODS
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All experimental procedures were approved by the Kansas State University Institutional Animal Care and Use Committee.
Animals
Twenty yearling crossbred steers with an average initial BW of 421.1 ± 3.6 kg were stratified by BW and randomly assigned to 1 of 4 treatments: 1) nonimplanted, control; 2) implanted with 120 mg of TBA and 24 mg of E2 (TBA/E2 group); 3) implanted with 25.7 mg of E2 (E2 group); or 4) implanted with 120 mg of TBA (TBA group). Beginning 21 d before the initiation of the study, steers were placed in individual feeding stalls and stepped onto a 93% concentrate diet offered ad libitum throughout the study. On d 0 (time of implantation), all steers were consuming the 93% concentrate diet. Biopsies of LM were taken from each animal on d 0, 7, 14, and 28, as described below.
LM Biopsy
Biopsies of the LM between the 10th and 13th rib were obtained from all steers on d 0, 7, 14, and 28. Samples were obtained from alternate sides. Briefly, steers were restrained in a hydraulic squeeze chute, hair was removed from the biopsy site, and a local anesthetic (lidocaine HCl, 20 mg/mL; 8 mL per biopsy site) was administered. The biopsy site was cleaned with 70% ethanol and sterile surgical gauze. A 1-cm incision was made with a sterile scalpel. Tissue was collected (1.0 g) from the LM with a sterile Bergstrom biopsy needle and immediately placed in 10 mL of a 5 M guanidine thiocyanate, 50 mM Tris-HCl, 25 mM EDTA, 0.5% lauryl sarcosine, and 1% β-mercaptoethanol solution in polypropylene tubes, homogenized, snap-frozen in liquid nitrogen, and stored at –80°C for subsequent RNA isolation. The incision site was closed with veterinary tissue glue. A topical antibiotic spray was applied to the incision site and then covered with a spray-on aluminum bandage. All steers were monitored for swelling 24 and 48 h after biopsy.
Sample Preparation and RNA Isolation from LM Biopsy Samples
Isolation of RNA from the thawed tissue homogenates was done by using procedures in routine use in our laboratory (Chomczynski and Sacchi, 1987; Pampusch et al., 2003). Isolated RNA was mixed with 0.5 vol of LiCl precipitation solution (7.5 M LiCl, Ambion, Austin, TX) and incubated at –20°C for 30 min. The solution was then centrifuged at 16,000 x g in a Microfuge microcentrifuge for 15 min. The resulting pellet was washed with 70% ethanol, dried, and resuspended in water. Samples were treated with DNase to remove any contaminating genomic DNA by using the DNA-Free kit (Ambion) following the manufacturer’s instructions (Pampusch et al., 2003). Concentration of RNA was determined by absorbance at 260 nm; RNA integrity was determined by electrophoresis of total RNA through a 1% agarose-formaldehyde gel, followed by ethidium bromide staining to allow visualization of 28S and 18S ribosomal RNA. The RNA was then reverse transcribed to produce first-strand complimentary DNA (cDNA) as described below.
Real-Time Reverse Transcription-PCR
Real-time reverse transcription-PCR was used to measure the quantities of IGF-I, IGFR-1, ER-, and AR mRNA relative to the quantity of cyclophilin mRNA in total RNA isolated from LM tissue from implanted and nonimplanted steers. The cDNA was produced from 1 µg of RNA by using TaqMan Reverse Transcription Reagents (Applied Biosystems, Foster City, CA) and the protocol recommended by the manufacturer. Random hexamers were used as primers in cDNA synthesis. Measurement of the relative quantity of the cDNA of interest was carried out by using SYBR Green PCR Master Mix (Applied Biosystems), 300 nM of the appropriate forward and reverse primers (Table 1), and 1 µL of the cDNA mixture. Assays were performed in the GeneAmp 7300 Sequence Detection System (Applied Biosystems) by using the thermal cycling parameters recommended by the manufacturer (40 cycles of 15 s at 95°C, and 1 min at 60°C). Primers were designed by using the Primer Design program (Applied Biosystems). Titration of cyclophilin, IGF-I, IGFR-1, ER-, and AR primers (300 nM forward and reverse primers) against increasing amounts of cDNA gave linear responses with slopes between -2.8 and -3.0. No-template controls were included in all assays; electrophoresis through a 1% agarose-formaldehyde gel, followed by ethidium bromide staining, was done to verify that each primer set produced only one amplicon of the appropriate size. To reduce the effect of assay-to-assay variation in the PCR assay, all values were standardized by expressing them relative to a standard muscle mRNA sample that was run on every real-time PCR assay. The amount of the mRNA of interest relative to the amount of cyclophilin mRNA in the same sample was first calculated and then expressed relative to the ratio of mRNA of interest to the amount of cyclophilin mRNA in a standard muscle RNA sample that was run on every assay.
Statistical Analysis
All statistical analyses were conducted with SAS Systems programs (SAS Inst. Inc., Cary, NC). Muscle gene expression data and BW were analyzed as a completely randomized block design by the mixed model procedure for repeated measures. The spatial power law for unequally spaced data was used as the covariance structure, and day of study was the repeated effect. Day 0 for each variable was used as a covariate. Dry matter intake was analyzed as a completely randomized block design by the mixed model procedure. The model included treatment as a fixed effect and block as a random effect. Results are reported as least squares means.
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RESULTS
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Feedlot Performance of Nonimplanted and Implanted Steers
The average BW of the control, E2, TBA, and TBA/E2 groups were similar on d 0 (421.1 ± 3.6 kg). Body weight of implanted steers tended (P = 0.09) to be greater than BW of control steers (Figure 1). There was a treatment x day interaction (P = 0.035) because BW of the TBA steers was greater than that of control steers by d 14 (P = 0.0299), and by d 28 all implanted groups were heavier than the group of control steers (P < 0.002). Dry matter intake was not different between the groups (P = 0.13) and averaged 18.7 ± 1.1 kg/d (data not shown).
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Figure 1. Covariantly adjusted average BW (using d-0 BW as the covariant) of control (CTL), estradiol 17-β (E2)-implanted, trenbolone acetate (TBA)-implanted, and TBA/E2-implanted steers on d 0, 7, 14, and 28. a,bWithin a day, points that do not contain a common letter designation are significantly different (P < 0.05). Individual symbols on the y-axis indicate the nonadjusted d-0 BW for each group. Pooled SEM = 4.33.
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IGF-I mRNA Levels in LM of Nonimplanted Steers and Steers Implanted with E2, TBA, or TBA/E2
Over the 28 d of this study, there was an effect of steroid treatment on LM IGF-I mRNA level (P = 0.019) and a day x treatment interaction effect (P = 0.076). On d 7, steers implanted with E2 had LM IGF-I levels that were 58% greater (P = 0.009) than the levels in control steers (Figure 2). On d 7, LM IGF-I mRNA levels also were greater in E2-implanted steers than in TBA-implanted (89%, P = 0.0035) or TBA/E2-implanted (69%; P = 0.0047) steers. Longissimus muscle IGF-I mRNA levels in steers implanted with TBA or with TBA/E2 were not different from levels in control steers on d 7. On d 14, there was no difference in the LM IGF-I levels among the groups. On d 28, steers implanted with E2 had greater (71%, P = 0.009) LM IGF-I mRNA levels than did control steers (Figure 2). Similarly, TBA/E2-implanted steers had greater (65%, P = 0.017) LM IGF-I mRNA levels than did control steers. Additionally, both E2- and TBA/E2-implanted steers had greater levels of LM IGF-I mRNA (71%, P = 0.022; and 65%, P = 0.024, respectively) than did steers implanted with TBA; however, there was no difference between the LM IGF-I mRNA levels in the TBA/E2- and E2-implanted steers (Figure 2). The LM IGF-I mRNA levels in control steers and in steers implanted with TBA were not different on d 28.
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Figure 2. Covariantly adjusted relative LM IGF-I mRNA level (adjusted by using d-0 IGF-I level as the covariant) of control (CTL), estradiol 17-β (E2)-implanted, trenbolone acetate (TBA)-implanted, and TBA/E2-implanted steers on d 0, 7, 14, and 28. a,bWithin a day, points that do not contain a common letter designation are significantly different (P < 0.05). Individual symbols on the y-axis indicate the nonadjusted d-0 relative LM IGF-I mRNA levels for each group. Pooled SEM = 0.061.
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Effects of TBA, E2, or TBA/E2 on ER-, AR, and IGFR-1 mRNA Levels in LM
It is possible that implantation with E2, TBA, or TBA/E2 alters the expression of IGFR-1, ER-, or AR receptors in muscle. Consequently, we examined the levels of mRNA for these receptors in the LM of implanted steers. Although some variation in mRNA levels for these receptors was observed, TBA, E2, or TBA/E2 implants did not affect the level of AR (P = 0.47), ER- (P = 0.83), or IGFR-1 (P = 0.87) mRNA in the LM of implanted steers compared with the levels in nonimplanted control steers (Figures 3, 4 and 5). However, there was a day effect for IGFR-1 (P = 0.036) and ER- (P = 0.010) mRNA, indicating that mRNA abundance for IGFR-1 and ER- increased with advancing days on feed.
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Figure 3. Covariantly adjusted relative LM IGF-I receptor (IGFR-1) mRNA level (adjusted by using d-0 IGFR-I level as the covariant) of control (CTL), estradiol 17-β (E2)-implanted, trenbolone acetate (TBA)-implanted, and TBA/E2-implanted steers on d 0, 7, 14, and 28. There were no significant differences in IGFR-1 levels between the treatment groups. Individual symbols on the y-axis indicate the nonadjusted d-0 relative LM IGFR-1 mRNA levels for each group. Pooled SEM = 0.06.
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Figure 5. Covariantly adjusted relative LM androgen receptor (AR) mRNA level (adjusted by using d-0 AR level as the covariant) of control (CTL), estradiol 17-β (E2)-implanted, trenbolone acetate (TBA)-implanted, and TBA/E2-implanted steers on d 0, 7, 14, and 28. There were no significant differences in AR levels between the treatment groups. Individual symbols on the y-axis indicate the nonadjusted d-0 relative LM AR mRNA levels for each group. Pooled SEM = 0.083.
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DISCUSSION
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Several studies have shown that a combined TBA/E2 implant is more effective than either TBA or E2 alone in stimulating the growth of feedlot steers; however, the mechanism of action of the individual steroids in the combined implant is not known (Hancock et al., 1991; Hayden et al., 1992). We previously reported that a combined TBA (120 mg) and E2 (24 mg) implant that increased rate of gain, feed efficiency, and muscle growth in feedlot steers also increased the circulating concentrations of IGF-I and the level of IGF-I mRNA in LM, but had no effect on muscle levels of hepatocyte growth factor, IGFBP-3, or myostatin mRNA (Johnson et al., 1996a,b; Pampusch et al., 2003). In view of reports that virally induced overexpression of IGF-I in muscle resulted in a 15% increase in muscle mass in young adult mice (Barton-Davis et al., 1998), and that IGF-I overexpression extended the replicative lifespan of satellite cells in culture (Barton-Davis et al., 1999; Chakravarthy et al., 2000), it is likely that steroid-induced increases in muscle IGF-I mRNA level play a role in the enhanced muscle growth observed in steers treated with a combined TBA/E2 implant. Currently, it is not clear whether E2, TBA, or the combination of the 2 steroids is responsible for the increased level of muscle IGF-I mRNA observed in TBA/E2-implanted steers.
Although the current study was not designed to assess the effects of the various implants on growth and performance, we did evaluate growth and DMI to ensure that the animals in the study were performing normally. As expected, based on previous studies (Johnson et al., 1993; Pampusch et al., 2003), animals receiving E2, TBA, or TBA/E2 implants grew more rapidly than nonimplanted controls during the 28 d of the study. Although the relatively small number of animals used in this study did not allow us to detect differences in growth between animals implanted with TBA, E2, or TBA/E2, these data established that the steers used in this study were responding to implantation.
Our current results show that implantation of yearling steers for 28 d with an implant containing 25.7 mg of E2 or a combined implant containing 120 mg of TBA plus 24 mg of E2 increased LM IGF-I mRNA levels. In contrast, implantation for 28 d with an implant containing 120 mg of TBA caused no increase in muscle IGF-I mRNA level. Consequently, TBA at this level apparently does not stimulate increased LM IGF-I mRNA levels in steers. This result is consistent with observations of the effects of androgens on muscle IGF-I mRNA levels, protein levels, or both in other species, including humans (Sheffield-Moore et al., 2006; Lewis et al., 2007; Venken et al., 2007); however, there also are reports that androgens cause increased muscle IGF-I levels (Lewis et al., 2002). In vitro studies also indicate that both E2 and TBA can stimulate IGF-I mRNA levels (Kamanga-Sollo et al., 2004). Those studies have shown that treatment of bovine satellite cell cultures with either E2 or TBA increases IGF-I mRNA levels (Kamanga-Sollo et al., 2004). Additionally, the IGF-I gene reportedly possesses an androgen response element in its regulatory region (Wu et al., 2007). Thus, it was somewhat surprising that TBA did not increase LM IGF-I mRNA levels in our study. Note, however, that in bovine satellite cell cultures, E2 is effective at concentrations 100 times less than the effective concentrations of TBA (Kamanga-Sollo et al., 2004). Thus, it is possible that the concentrations of TBA in the muscle of TBA-implanted steers do not reach the concentration required to stimulate increased IGF-I mRNA levels.
Our data also show that the LM IGF-I mRNA levels are not different in steers implanted with E2 or with TBA/E2. This finding is consistent with the observation that TBA, at the level used in the combined TBA/E2 implant used in this study, does not increase LM IGF-I mRNA level.
Even though our data show that TBA does not stimulate increased LM IGF-I mRNA levels, TBA/E2 implants are more effective than either TBA or E2 alone in stimulating growth in feedlot steers (Hancock et al., 1991; Hayden et al., 1992). Consequently, TBA must be contributing to enhanced muscle growth via a mechanism that does not involve increased muscle IGF-I levels. We have shown that inhibition of the Raf-1/MAPK kinase (MEK)1/2/ERK1/2, and the phosphatidylinositol 3-kinase/Akt pathways completely suppresses TBA-stimulated proliferation in bovine satellite cell cultures (Kamanga-Sollo et al., 2008). Thus, TBA may affect muscle growth by stimulating these pathways.
It is possible that implantation with E2, TBA, or TBA/E2 alters the expression of growth factors and or receptors other than IGF-I that are known to affect muscle growth, muscle differentiation, or both. We previously reported that implantation with TBA/E2 did not alter the levels of myostatin, hepatocyte growth factor, or IGFBP-3 mRNA in the muscle of implanted steers (Pampusch et al., 2003). To further explore the role of specific receptors in E2-, TBA-, and TBA/E2-stimulated muscle growth, we examined the effects of these implants on IGFR-1, ER-, and AR receptor mRNA in muscle in the present study. None of the implants investigated affected the LM AR, ER, or IGFR-1 mRNA levels. Although failure to detect a change in mRNA level for a particular receptor does not prove conclusively that the level of the receptor is not changed, it does indicate that any change in receptor level does not occur because of increased mRNA production.
In summary, our current data show that, although TBA/E2 implants increased LM IGF-I mRNA levels, TBA implants containing the same level of TBA found in the combined implant did not increase LM IGF-I mRNA levels. Additionally, E2 implants containing approximately the same amount of E2 found in the combined implant increased the LM IGF-I mRNA level to the same degree as the combined implant. Consequently, we conclude that E2 is responsible for the increased LM IGF-I mRNA level observed in steers treated with the combined TBA/E2 implant examined in this study.
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Footnotes
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1 This research was supported by National Research Initiative Competitive Grant 2006-35206-16663 from the USDA Cooperative State Research, Education, and Extension Service and by the Minnesota Agricultural Experiment Station (University of Minnesota, St. Paul, MN) and Kansas Agricultural Experiment Station (Kansas State University, Manhattan, KS). 
2 Corresponding author: wdayton{at}umn.edu
Received for publication April 4, 2008.
Accepted for publication July 20, 2008.
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LITERATURE CITED
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Abstract
INTRODUCTION
