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

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 6 weeks 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; 18-30 years) were randomized in a double-blinded fashion to receive placebo (P, saline n = 8) or the GnRH analogue, Goserelin [Zoladex (Z), 3.6 mg, n = 8], injections, before 6 weeks 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 +/- 3.1 kg, P = 0.61 vs. P: 55.9 +/- 1.7 to 57.4 +/- 1.7 kg, 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 +/- 0.36 cm, P > 0.99 vs. P: 2.74 +/- 0.32 to 2.91 +/- 0.32 cm, 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. AKT(ser473): Z: 2.74 +/- 0.6, P = 0.2 vs. P: 5.5 +/- 1.1 fold change, P < 0.001, ES = 0.54 and mTORC1(ser2448): 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%center dot day(-1), P = 0.99 vs. P: 1.5 +/- 0.12 to 2.0 +/- 0.15%center dot day(-1), P = 0.01, ES = 0.97) and (extrapolated) muscle protein breakdown (Z: 93.16 +/- 7.8 vs. P: 129.1 +/- 13.8 g center dot 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 +/- 1.1 g center dot 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.

Automated summary

This study investigates the effects of endogenous testosterone depletion on muscle hypertrophic responses to resistance exercise training (RET), and finds that sufficient endogenous testosterone plays a crucial role in up-regulating molecular transducers of muscle growth.