**Background:** Tall fescue infected with the endophyte fungus Epichloë coenophiala produces ergot alkaloids that cause fescue toxicosis in cattle, characterized by reduced feed intake, lower weight gains, vasoconstriction, and hormonal disruption. Ergot alkaloids contain an ergoline ring similar to biogenic amines (serotonin, dopamine, norepinephrine), allowing them to bind to these receptors and elicit negative effects. The synthetic ergot alkaloid bromocriptine activates D2 dopamine receptors and α2 adrenergic receptors, potentially inhibiting insulin secretion. Steroidal implants (trenbolone acetate + estradiol 17β) are used to improve performance in cattle grazing infected pastures, and are believed to increase IGF-1 signaling and mTOR pathway activation. This study tested whether bromocriptine decreases muscle protein synthesis through inhibitory action on the mTOR pathway and whether anabolic implants can alleviate these effects.
**Methods:** Thirty-two Holstein steers (initial BW 332.6 ± 54.6 kg) were used in a 35-day randomized complete block design with 4 treatments in a 2×2 factorial: CON (no implant, carrier injection), BROMO (no implant, bromocriptine 0.1 mg/kg BW IM every 3 days), IMP (implant with 120 mg TBA + 24 mg estradiol 17β, carrier injection), and B+I (implant + bromocriptine). Intake was restricted to 1.5× maintenance energy requirement to eliminate confounding by DMI effects. On days 27-32, steers were moved to metabolism stalls for urine collection. Whole-body protein turnover was determined using a single pulse dose of [15N]glycine (3.0 mg/kg BW) into the jugular vein on day 28, with urine sampled every 12 h for 96 h. On day 35, blood and obliquus externus abdominis muscle samples were collected before (basal) and 60 min after (stimulated) an IV glucose challenge (0.25 g glucose/kg BW). Western immunoblot analysis measured total and phosphorylated mTOR (Ser2448), S6K1 (Thr389), and 4E-BP1 (Thr37/46). Plasma prolactin, glucose, and insulin were measured. Data were analyzed using SAS mixed/glimmix procedures with bromocriptine, implant, and their interaction as fixed effects and block as random.
**Key Results:** DMI did not differ between treatments (p ≥ 0.22). Bromocriptine decreased ADG by approximately 16% (p = 0.01), while implants increased ADG by 48% (with bromocriptine) and 56% (without bromocriptine) (p < 0.0001). Prolactin AUC was significantly lower in bromocriptine-treated steers (1,803 ± 347 vs. 3,278 ± 367; p = 0.002). Urea excretion was lower in implanted steers (38.88-44.28 vs. 50.60-57.27 g/day; p = 0.006) but unaffected by bromocriptine (p = 0.13). 15N fractional recovery was lower in implanted steers (p = 0.03). Protein turnover tended to be lower with implants (131.7 ± 7.8 vs. 141.9 ± 7.5 g N/day; p = 0.10), but protein synthesis was unaffected by either treatment (p ≥ 0.47). Bromocriptine increased insulin AUC (10,496 ± 818 vs. 8,052 ± 818; p = 0.04) and tended to increase glucose AUC (17,155 ± 687 vs. 16,206 ± 687 mg/dL; p = 0.09). Time to peak insulin tended to be longer with bromocriptine (18 ± 2 vs. 15 ± 1 min; p = 0.09). Bromocriptine increased basal total mTOR abundance (p = 0.05) and post-infusion phosphorylated mTOR (p = 0.04) but did not affect mTOR activation status. Post-infusion total S6K1 was lower with bromocriptine (p = 0.05). Implant decreased post-infusion total 4E-BP1 (p = 0.04), phosphorylated 4E-BP1 (p = 0.02), and 4E-BP1 activation status (p = 0.01). Bromocriptine did not affect S6K1 or 4E-BP1 phosphorylation.
**Clinical Implications:** This study demonstrates that ergot alkaloids (modeled by bromocriptine) do not directly inhibit muscle protein synthesis or mTOR pathway activation in cattle when feed intake is controlled. Instead, the negative effects on growth appear to stem from disrupted glucose homeostasis and insulin sensitivity, suggesting that ergot alkaloids impair energy metabolism rather than protein accretion pathways. Steroidal implants improve weight gain and nitrogen retention primarily through decreased protein degradation rather than increased synthesis, and this effect persists even in the presence of ergot alkaloids. These findings indicate that management strategies for fescue toxicosis should focus on maintaining feed intake and addressing glucose/insulin dysregulation, while steroidal implants remain effective for improving growth performance. The study also reveals that the growth-promoting effects of estradiol/TBA implants may involve mechanisms beyond mTOR pathway activation, possibly through IGF-1 signaling via alternative pathways (MEK/ERK, PI3K/Akt/FoxO).