Potential role of G-protein-coupled receptor 30 (GPR30) in estradiol-17β-stimulated IGF-I mRNA expression in bovine satellite cell cultures
Introduction
Both androgenic and estrogenic steroids are routinely used to enhance muscle growth in domestic meat producing animals, in particular cattle [1]. Additionally, androgens reduce loss of muscle mass and strength in aging or hypogonadal men [2], [3]; and estrogen replacement therapy in postmenopausal women reportedly enhances both muscle mass and strength [4], [5], [6]. Feedlot steers implanted with a combined implant containing 120 mg of the synthetic androgen trenbolone acetate (TBA) and 24 mg of 17β-estradiol (E2), exhibited increased rate of gain (20–25%), increased feed efficiency (15–20%), increased carcass protein, and increased longissimus muscle area [7]. Circulating IGF-I concentrations and muscle IGF-I mRNA levels also were significantly increased by seven days after implantation [8]. Additionally, approximately 50% more actively proliferating satellite cells were isolated from the semimembranosus muscles of E2/TBA implanted steers than from the same muscles of non-implanted, control steers [9]. Both the increased muscle IGF-I mRNA and increased satellite cell number may be significant in view of reports that virally induced over expression of IGF-I in muscle resulted in a 15% increase in muscle mass in young adult mice [10] and that IGF-I over expression extended the replicative lifespan of satellite cells in culture [11], [12].
E2 stimulates expression of IGF-I mRNA in a number of tissues [13], [14], [15], [16]. Studies evaluating the mechanism by which E2 stimulates expression of chicken IGF-I mRNA have shown that, even though the IGF-I gene does not contain a traditional estrogen response element (ERE) in its regulatory region, E2-stimulation of IGF-I mRNA expression can occur via a pathway involving the AP-1 enhancer [17]. In tissues studied to date, E2 stimulation of IGF-I mRNA expression is abrogated by treatment with the pure E2 antagonist ICI 182 780 [18], [19], [20]. However, the ability of E2 and/or agonists or antagonists to affect cellular responses via the AP-1 site varies dramatically with different cell types [21]. In addition to the classical estrogen receptors, G-protein-coupled receptor 30 (GRP30) [22], may play a role in mediating the actions of estrogen [23]. Muscle tissue contains GPR30 mRNA [24], [25], [26] and immunohistochemical studies have localized GPR30 receptor protein in skeletal muscle cells [27].
Androgen treatment also has been shown to increase IGF-I mRNA expression [16]. Recently, an androgen response element (ARE) has been identified in the promoter region of the IGF-I gene [28], suggesting that androgen receptor–ligand complex may interact with this ARE to stimulate transcription of the IGF-I gene.
We have previously shown that both E2 and TBA treatment cause a concentration-dependent increase in IGF-I mRNA expression by cultured bovine muscle satellite cells (BSC) [16]. Here, we have explored the mechanism responsible for this increase by evaluating the effects of ICI 182 780 (an estrogen receptor antagonist) and flutamide (an androgen receptor inhibitor) on E2 or TBA-stimulated IGF-I mRNA expression, respectively, in BSC cultures. Additionally, in order to determine if E2 must enter the cell in order to stimulate IGF-I mRNA expression and proliferation, we have examined the effects of BSA-conjugated E2 (which cannot cross the cell membrane) on IGF-I expression and proliferation in BSC cultures. We also have assessed the ability of the GPR30 agonist, G1 [29], to stimulate proliferation and IGF-I mRNA expression in BSC cultures.
Section snippets
Bovine satellite cell isolation
Satellite cell isolation was done as described previously [30], [31], [32]. Steers were euthanized using procedures approved by the Kansas State University Institutional Animal Care and Use Committee. Using sterile techniques, approximately 500 g of the semimembranosus muscle were dissected out and transported to the cell culture laboratory. Subsequent procedures were conducted in a sterile field under a tissue culture hood. After removal of connective tissue the muscle was passed through a
Effect of flutamide on TBA-stimulated IGF-I expression in BSC
We have previously shown that treatment of BSC cultures with 10 nM TBA for 48 h results in a significant increase in IGF-I mRNA expression [16]. Flutamide inhibits the action of the androgen receptor and consequently inhibits the action of androgens on cell function. Fig. 1 shows the effect of flutamide treatment on IGF-I mRNA expression in BSC cultures in the presence or absence of 10 nM TBA. Flutamide treatment has no effect on IGF-I mRNA expression in control cultures containing 10% FBS and no
Discussion
Studies in humans have shown that testosterone treatment increases IGF-I mRNA levels in skeletal muscle [43], [44]. Similarly, comparison of IGF-I mRNA levels in the splenius muscle of castrated and intact twin lambs showed higher levels of IGF-I mRNA in the muscle of intact sheep [45]. Recently, an androgen response element has been identified in the promoter region of the IGF-I gene [28], suggesting that androgen receptor–ligand complex may interact with this ARE to stimulate transcription of
Acknowledgements
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.
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