@article { , title = {Pharmacological hypogonadism impairs molecular transducers of exercise-induced muscle growth in humans}, abstract = {Background: The relative role of skeletal muscle mechano-transduction in comparison with systemic hormones, such as testosterone (T), in regulating hypertrophic responses to exercise is contentious. We investigated the mechanistic effects of chemical endogenous T depletion adjuvant to 6weeks of resistance exercise training (RET) on muscle mass, function, myogenic regulatory factors, and muscle anabolic signalling in younger men. Methods: Non-hypogonadal men (n=16; 18–30years) were randomized in a double-blinded fashion to receive placebo (P, saline n=8) or the GnRH analogue, Goserelin [Zoladex (Z), 3.6mg, n=8], injections, before 6weeks of supervised whole-body RET. Participants underwent dual-energy X-ray absorptiometry (DXA), ultrasound of m. vastus lateralis (VL), and VL biopsies for assessment of cumulative muscle protein synthesis (MPS), myogenic gene expression, and anabolic signalling pathway responses. Results: Zoladex suppressed endogenous T to within the hypogonadal range and was well tolerated; suppression was associated with blunted fat free mass [Z: 55.4±2.8 to 55.8±3.1kg, P=0.61 vs. P: 55.9±1.7 to 57.4±1.7kg, P=0.006, effect size (ES)=0.31], composite strength (Z: 40±2.3\% vs. P: 49.8±3.3\%, P=0.03, ES=1.4), and muscle thickness (Z: 2.7±0.4 to 2.69±0.36cm, P>0.99 vs. P: 2.74±0.32 to 2.91±0.32cm, P<0.0001, ES=0.48) gains. Hypogonadism attenuated molecular transducers of muscle growth related to T metabolism (e.g. androgen receptor: Z: 1.2 fold, P>0.99 vs. P: 1.9 fold, P<0.0001, ES=0.85), anabolism/myogenesis (e.g. IGF-1Ea: Z: 1.9 fold, P=0.5 vs. P: 3.3 fold, P=0.0005, ES=0.72; IGF-1Ec: Z: 2 fold, P>0.99 vs. P: 4.7 fold, P=0.0005, ES=0.68; myogenin: Z: 1.3 fold, P>0.99 vs. P: 2.7 fold, P=0.002, ES=0.72), RNA/DNA (Z: 0.47±0.03 to 0.53±0.03, P=0.31 vs. P: 0.50±0.01 to 0.64±0.04, P=0.003, ES=0.72), and RNA/ASP (Z: 5.8±0.4 to 6.8±0.5, P>0.99 vs. P: 6.5±0.2 to 8.9±1.1, P=0.008, ES=0.63) ratios, as well as acute RET-induced phosphorylation of growth signalling proteins (e.g. AKTser473: Z: 2.74±0.6, P=0.2 vs. P: 5.5±1.1 fold change, P<0.001, ES=0.54 and mTORC1ser2448: Z: 1.9±0.8, P>0.99 vs. P: 3.6±1 fold change, P=0.002, ES=0.53). Both MPS (Z: 1.45±0.11 to 1.50±0.06\%·day−1, P=0.99 vs. P: 1.5±0.12 to 2.0±0.15\%·day−1, P=0.01, ES=0.97) and (extrapolated) muscle protein breakdown (Z: 93.16±7.8 vs. P: 129.1±13.8g·day−1, P=0.04, ES=0.92) were reduced with hypogonadism result in lower net protein turnover (3.9±1.1 vs. 1.2±1.1g·day−1, P=0.04, ES=0.95). Conclusions: We conclude that endogenous T sufficiency has a central role in the up-regulation of molecular transducers of RET-induced muscle hypertrophy in humans that cannot be overcome by muscle mechano-transduction alone.}, doi = {10.1002/jcsm.12843}, eissn = {2190-6009}, issn = {2190-5991}, issue = {2}, journal = {Journal of Cachexia, Sarcopenia and Muscle}, pages = {1134-1150}, publicationstatus = {Published}, publisher = {Wiley}, url = {https://nottingham-repository.worktribe.com/output/7536568}, volume = {13}, keyword = {Physiology (medical), Orthopedics and Sports Medicine}, year = {2022}, author = {Gharahdaghi, Nima and Rudrappa, Supreeth and Brook, Matthew S. and Farrash, Wesam and Idris, Iskandar and Aziz, Muhammad Hariz Abdul and Kadi, Fawzi and Papaioannou, Konstantinos and Phillips, Bethan E. and Sian, Tanvir and Herrod, Philip J. and Wilkinson, Daniel J. and Szewczyk, Nathaniel J. and Smith, Kenneth and Atherton, Philip J.} }