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 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%·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 ± 13.8 g·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·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.

Keywords: Exercise training; Hypertrophy; Muscle protein synthesis; Testosterone.

Figure 1

Detailed schematic of the study protocol.

Figure 2

Induced hypogonadism attenuates muscle growth and functional adaptations to RET. Time‐course of changes in (I) plasma T levels in pre vs. post RET in P group and over the study measures in Z group, (II) muscle mass and body composition, (III) muscle architecture, (IV) muscle fibre type features and correlation between fibre type and quadriceps CSA, and (V) changes in dynamic and static strength from baseline to Week 6 in Zoladex (Z) and placebo (P) groups. Values are means ± SEM. a = significantly different from baseline; b = significantly different between the two groups (Z: zoladex, P: placebo), P < 0.05. CSA, cross‐sectional area; FFM, fat free mass; Lf, fascicle length; MT, muscle thickness; MVC, maximal voluntary contraction; PA, pennation angle; RET, resistance exercise training; T, testosterone; TFP, total fat percentage. See also Figures S1 and S2.

Figure 3

Hypogonadism attenuates muscle protein turnover increases to RET. Values are means ± SEM. a = significantly different from baseline; b = significantly different between the two groups (Z: zoladex, P: placebo), P < 0.05. ABR, absolute breakdown rate; ASR, absolute synthetic rate; FGR, fractional growth rate; FSR, fractional synthesis rate; MPS, muscle protein synthesis; RET, resistance exercise training. See also Figure S3.

Figure 4

Mechano‐signals cannot bypass blunted translational efficiency in hypogonadism after RET. Values are means ± SEM. a = significantly different from baseline; b = significantly different between the two groups (Z: zoladex, P: placebo), c = significantly different from Week 0, P < 0.05. RET, resistance exercise training.

Figure 5

Hypogonadism impaired RET‐induced myogenic and androgenic, but not mitochondrial adaptations. (A) Heatmap of the changes in T metabolism, anabolism, myogenic, and myogenesis inhibitor gene expression from baseline to Week 6 of RET in Z and P. (B) Venn diagram of the overlap of differentially expressed genes briefly increased in Z, P, both, or neither. Values are means of fold changes normalized to a housekeeping gene (i.e. RPL13A), which exhibited high transcriptional stability over the study (between groups: P = 0.8; within both groups: P > 0.9). a = significantly different from baseline; b = significantly different between the two groups (Z: zoladex, P: placebo), P < 0.05. RET, resistance exercise training.