Molecular regulation of skeletal muscle metabolism by testosterone and exercise in younger and older age
Year: 2020
Type: dissertation
Study design: Clinical Trial
Abstract: 3.1 Background: The role of endogenous testosterone (T) in mediating hypertrophic responses to resistance exercise training (RET) remains contentious with correlative studies suggesting a limited role, and others a more central role. We thus investigated the physiological and mechanistic effects of chemical endogenous testosterone depletion adjuvant to 6-wks of RET on muscle mass, function, myogenic regulatory factors, muscle anabolic signalling, and protein synthesis in younger men. Methods: Sixteen non-hypogonadal healthy young men (18-30 y, BMI≤30 kg.m- 2, serum T>230 ng·dl-1) were randomised in a double-blinded fashion to receive either: placebo (P, saline n=8) or the GnRH analogue, Goserelin (Zoladex (Z) (3.6 mg, n=8)) injections before undertaking 6-wks of RET (6-exercises, 3-sets, 8-10 reps, 80% 1-RM). Participants underwent dual-energy x-ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee-extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D2O) and breakdown (extrapolated). Results: Provision of Zoladex during RET suppressed endogenous testosterone (Z: 45.2±4, vs. P: 323±30 ng.dl-1, P<0.001). The Zoladex group exhibited blunted whole-body (Z: 55±3 to 56±3 kg, P=0.6 vs. P: 56±2 to 58±2 kg, P=0.006) and appendicular fat free mass (FFM) (Z: 8.2±0.3 to 8.4±0.4, P>0.9 vs. P: 7.6±0.3 to 8.3±0.3kg·m-2, P=0.07). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross-section area with RET occured to a greater extent in placebo (P<0.05) and composite strength gains (Z: 40±2 vs. P: 50±3%, P=0.03) increased significantly more in the placebo group. Reductions in body fat percentage were only evident in the placebo group (Z: 23±2 to 24±2%, P=0.2 vs. P: 24±3 to 23±3%, P=0.04). The placebo group exhibited augmented gene expression related to testosterone metabolism (e.g. Androgen Receptor: 1.8- fold; HSD17B3: 2.8-fold, P<0.05); anabolism/myogenesis (e.g. IGF-1EA (3.3- fold), Myogenin (2.6-fold), Myf5 (2.6-fold), c-Met (2.7-fold), P<0.05) in addition to RNA/DNA (P:0.5±0.1 to 0.6±0.1, P=0.0003 vs. Z:0.5±0.1 to 0.5±0.1, P=0.3), and RNA/ASP ratio (P:6.5±0.2 to 8.9±1.1, P=0.008 vs. Z:5.8±0.4 to 6.8±0.5, P>0.9). Also, acute RET-induced phosphorylation of AKTser473 (Z: 4.9±1.6-fold, P=0.7 vs. P: 10.1±5.3-fold, P=0.003) and mTORC1ser2448 (Z: 2.5±1.3-fold, P>0.9 vs. P: 4.8±2.1-fold, P=0.03) were attenuated in the Zoladex group. Both MPS (P: 2.01±0.1 vs. Z: 1.54±0.1%·day−1, P=0.01) and MPB rates (P: 129.1±13 vs. Z: 93.1±7.8 g·day-1, P=0.04) were higher in placebo group, which led to higher net turnover and protein accretion (P: 3.9±1.1 vs. Z: 1.2±1.1 g·day-1, P=0.04). Conclusions: Chemical testosterone depletion during RET blunted muscle anabolic signalling, testosterone processing enzyme and pro-myogenic gene expression, perhaps explaining attenuated muscle growth in this group. Thus, decreasing endogenous levels of testosterone coupled to RET attenuates numerous positive adaptations to RET - thereby, demonstrating, at least, permissive importance of endogenous testosterone in regulating muscle hypertrophy. 4.1 Background: The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia) and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy, and physiological and molecular impacts of T therapy adjuvant to short-term RET remain poorly defined. Methods: Eighteen non-hypogonadal healthy older men, 65-75 y, were assigned in a random double-blinded fashion to receive, bi-weekly, either placebo (P, saline, n=9) or T (Sustanon 250 mg, n=9) injections over 6-weeks whole-body RET (3-sets of 8-10 reps at 80% 1-RM). Subjects underwent dual- energy x-ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee-extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D2O) and breakdown (extrapolated). Results: T adjuvant to RET, augmented total fat free mass (FFM) (P=0.007), legs fat free mass (P=0.02), and appendicular FFM (P=0.001) gains, while decreasing total fat mass (P=0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross-section area with RET occured to a greater extent in T (P<0.05). Total strength (P=0.0009) and maximal voluntary contract (e.g. knee extension at 70°) (P=0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13±0.21%·day−1 vs. P: 1.34±0.13%·day−1, P=0.0009) and absolute breakdown rates (T: 140.2±15.8 vs. P: 90.2±11.7g·day-1, P=0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3±1.4g·day-1 vs. P: 1.9±1.2 g·day-1, P=0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); mRNA expression relating to T metabolism (Androgen Receptor: 1.4-fold; Srd5a1: 1.6-fold; AKR1C3: 2.1-fold; HSD17β3: 2- fold); IGF-1-signalling (IGF-1Ea (3.5-fold), IGF-1Ec (3-fold) and myogenic regulatory factors (MRF); as well the activity of anabolic signalling (e.g. mTOR, AKT, RPS6; P<0.05) were all upregulated with T therapy. Only T up-regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (Tfam) (1.41±0.2-fold, P=0.0002), in addition to PGC1-α mRNA (1.19±0.21-fold, P=0.037). Conclusions: Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while upregulating myogenic gene programming, myocellular translational efficiency and capacity - collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short-term intervention to improve muscle mass/ function in older non- hypogonadal men. 5.1 Introduction: Insulin resistance is a risk factor for many metabolic diseases, coincident with the established pandemic of obesity, worldwide. The main behavioural strategies to overcome insulin resistance remain diet and exercise training. However, the “andropause”, so-called due to age-related testosterone (T) depletion has been associated with impaired glycaemic control – leading to investigations of the role of testosterone in regulating insulin sensitivity which is unclear. Therefore, the aim of this study was to investigate the role of endogenous testosterone during 6-wks of resistance exercise training (RET), in relation to glycaemic control in healthy young men. Methods: 16 healthy non-hypogonadal men (~18-30y, BMI≤30kg.m-2, serum T>230 ng·dl-1) were recruited with the aim of determining the role of endogenous suppression of testosterone in relation to RET-induced improvements in glycaemic control in younger men. To do so, the participants were assigned in a randomised double-blinded fashion to receive injection of either: placebo (P; saline, n=8) or the GnRH analogue, Zoladex 3.6mg (Z; n=8). All subjects underwent 6-wks whole body RET (3-sets, 8-10 reps at 80% 1-RM) with 75g oral glucose tolerance testing (OGTT baseline, ~5 days after injection and after RET), and Dual-energy X-ray Absorptiometry (DXA) to assess glycaemic control and body composition, respectively. Results: Provision of Zoladex significantly reduced total testosterone in Zoladex (vs. placebo) throughout RET. Total fat free mass (FFM) increased significantly following 6-wks RET in placebo (55.9±1.7 to 57.4±1.7kg, P=0.006), but not in Zoladex (55.4±2.8 to 55.8±3.1kg). Over 6-wks of RET, placebo group showed decreased (2381±1013 mU-1.2h-1, P=0.009) insulin area under curve (AUC). Further, measures of C-Peptide highlighted a decreasing trend in placebo compared to Zoladex (551±57 ng.ml-1 vs. 789±116 ng.ml-1, P=0.08). Additionally, Cederholm index of peripheral insulin sensitivity in placebo showed an increase after RET (61.7±4.7 vs. 74.5±3.7 mg⋅L2⋅mmol⋅L−1⋅mU−1⋅min−1, P<0.05). Finally, Matsuda index of insulin sensitivity in placebo yielded significant increases based on fold-change from baseline OGTT to OGTT after RET (9.9±2.4 vs 12.8±3.2, P<0.05). Conclusion: Suppressed endogenous testosterone (Zoladex), attenuated insulin sensitivity (supported by c-peptide) in young men, during RET. Thus, endogenous testosterone is a permissive regulator of RET-induced improvements in insulin sensitivity and glycaemic control.
Author: Gharahdaghi, Nima
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7218109829