Exogenous testosterone therapy overcomes anabolic blunting to resistance-type exercise in older men

Physiology 2019 (Aberdeen, UK) (2019) Proc Physiol Soc 43, C059

Oral Communications: Exogenous testosterone therapy overcomes anabolic blunting to resistance-type exercise in older men

N. Gharahdaghi1, S. Rudrappa1, M. S. Brook1, I. Idris1, M. Aziz1, B. Phillips1, D. J. Wilkinson1, N. J. Szewczyk1, K. Smith1, P. J. Atherton1

1. Medical Sciences & Graduate Entry Medicine, University of Nottingham, Derby, United Kingdom.

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The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia) and frailty. Conversely, two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Given the andropause and blunted hypertrophic responses to RET with advancing age1, the efficacy, and physiological and molecular impacts of T therapy adjuvant to short-term RET remain poorly defined. 18 non-hypogonadic healthy older men, 65-75y, BMI≤30kg.m-2 (serum T>230 ng.dl-1) were assigned in a random double-blinded fashion to receive bi-weekly: placebo (P, saline, n=9) or T (Sustanon 250-mg, n=9) injections over 6-weeks of whole-body RET (6 exercises, 3-sets, 8-10reps at 80% 1-RM). Subjects underwent Dual-energy X-ray Absorptiometry, ultrasound of m.vastus lateralis (VL) architecture and Oral Glucose Tolerance Testing; finally, m.vastus biopsies were taken to quantify myogenic gene expression and activation of insulin/anabolic pathways, and muscle protein synthesis (D2O) and breakdown (extrapolated). T adjuvant to RET, augmented whole-body (53.0±1.7 to 56.0±5.2, P<0.0001 vs. 54.1±6.3 to 54.8±5.8 kg, P>0.05) and appendicular lean mass gains (7.8±0.3 to 8.3±0.3 vs. 7.9±0.3 to 8.0±0.3 kg.m2, P<0.0001) while decreasing body fat (22.5±2.0 to 21.3±1.8 vs. 24.7±2.8 to 24.5±2.7kg, P=0.01). T also augmented VL thickness gains (2.3±0.07 to 2.6±0.04 vs. 2.3±0.1 to 2.4±0.09 cm, P<0.0001) and fascicle-length (7.1±0.2 to 7.9±0.2, P<0.0001 vs. 7.7±0.1 to 8.1±0.1 cm, P<0.0001) in addition to dynamic strength (T:+60.8±3.6 vs. P:+43.25±2.4%, P=0.0009). Mechanistically, both muscle protein synthesis rates (T: 2.13±0.21 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 (T:8.3±1.4 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); IGF-1-signalling (IGF-1Ea (3.5-fold), IGF-1Ec (3-fold) and myogenic regulatory factors (MRF); and 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). Finally, T augmented insulin sensitivity (e.g. Cederholm index: T: 57.3±5 to 68.6±5.3 vs. P: 49.1±3.7 to 57.1±5.1 mg.L2.mmol.L−1.mU−1.min−1, P=0.02) 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. Thus, T coupled with RET is an effective short-term intervention to improve muscle mass/ function in older non-hypogonadal men.



Where applicable, experiments conform with Society ethical requirements.

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