Pharmacological hypogonadism impairs molecular transducers of exercise-induced muscle growth in humans

Gharahdaghi, Nima; Rudrappa, Supreeth; Brook, Matthew S.; Farrash, Wesam; Idris, Iskandar; Aziz, Muhammad Hariz Abdul; Kadi, Fawzi; Papaioannou, Konstantinos; Phillips, Bethan E.; Sian, Tanvir; Herrod, Philip J.; Wilkinson, Daniel J.; Szewczyk, Nathaniel J.; Smith, Kenneth; Atherton, Philip J.

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.

Citation

Gharahdaghi, N., Rudrappa, S., Brook, M. S., Farrash, W., Idris, I., Aziz, M. H. A., …Atherton, P. J. (2022). Pharmacological hypogonadism impairs molecular transducers of exercise-induced muscle growth in humans. Journal of Cachexia, Sarcopenia and Muscle, 13(2), 1134-1150. https://doi.org/10.1002/jcsm.12843

• Journal Article Type: Article
• Acceptance Date: Sep 30, 2021
• Online Publication Date: Mar 1, 2022
• Publication Date: Apr 1, 2022
• Deposit Date: Mar 4, 2022
• Publicly Available Date: Mar 4, 2022
• Journal: Journal of Cachexia, Sarcopenia and Muscle
• Print ISSN: 2190-5991
• Electronic ISSN: 2190-6009
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 2
• Pages: 1134-1150
• DOI: https://doi.org/10.1002/jcsm.12843
• Keywords: Physiology (medical); Orthopedics and Sports Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/7536568
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12843