Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men

Abstract

BackgroundThe 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.MethodsEighteen non‐hypogonadal healthy older men, 65–75 years, were assigned in a random double‐blinded fashion to receive, biweekly, either placebo (P, saline, n = 9) or T (Sustanon 250 mg, n = 9) injections over 6 week whole‐body RET (three sets of 8–10 repetitions at 80% one‐repetition maximum). 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).ResultsTestosterone adjuvant to RET augmented total fat‐free mass (P=0.007), legs fat‐free mass (P=0.02), and appendicular fat‐free mass (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). Sum 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 g·day−1 vs. P: 90.2 ± 11.7 g·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 ± 1.4 g·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; and HSD17β3: two‐fold); insulin‐like growth factor (IGF)‐1 signalling [IGF‐1Ea (3.5‐fold) and IGF‐1Ec (three‐fold)] and myogenic regulatory factors; and the activity of anabolic signalling (e.g. mTOR, AKT, and RPS6; P < 0.05) were all up‐regulated with T therapy. Only T up‐regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (1.41 ± 0.2‐fold, P=0.0002), in addition to peroxisome proliferator‐activated receptor‐γ co‐activator 1‐α mRNA (1.19 ± 0.21‐fold, P=0.037).ConclusionsAdministration of T adjuvant to RET enhanced skeletal muscle mass and performance, while up‐regulating 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.

Testosterone Promotes the Proliferation of Chicken Embryonic Myoblasts Via Androgen Receptor Mediated PI3K/Akt Signaling Pathway

“…Reports indicated that T can increase muscle mass and decrease the amount of fat in a dose-dependent manner in young and older men [6,9,21]. The increase in muscle mass was due to hypertrophy of myofibers with response to T [13].…”

“…T and its synthetic homologues have been used clinically and illegally to increase muscle mass [6,22]. In response to T administration, the number of proliferating cell nuclear antigen (PCNA) positive satellite cells increased in human skeletal muscle [22].…”

“…A series of myogenesis events take place as a result of the activation of specific signalling pathways and up-regulation of MRFs [5]. Studies have reported that T replacement significantly enhanced muscle strength and increased muscle mass in clinics [6,7]. Skeletal muscle regeneration with T was also observed in both young and aged mice post cardiotoxin injury, which resulted in an increase of satellite cells activation and number [8].…”

Associations between Plasma Branched Chain Amino Acids and Health Biomarkers in Response to Resistance Exercise Training Across Age

“…It is noted that lean mass gains were not evident in our older participants, and work from our lab shown this may indeed be due to anabolic resistance [ 37 ], which itself is multi-faceted (reduced translational capacity, hormonal efficiency and MPS with increased MPB), however RET still remains the most effective method of counteracting the age-related declines in loss of lean mass [ 38 ], particularly if it is combined with, for example, exogenous testosterone administration [ 39 ] or protein supplementation [ 40 , 41 ].…”

Importance of Assessing Muscular Fitness in Secondary Care

“…Although testosterone supplementation in older men has been shown to improve body composition, yet the effects on muscular strength or physical function are still conflicting (Endo et al, 2020). It has been shown that testosterone replacement therapy does not offer any benefit beyond resistance exercise alone in elderly patients with low to normal serum testosterone, but may be an effective short-term intervention to overcome age-related deficits in adaptive responses to resistance training (Gharahdaghi et al, 2019). However, because of potential adverse events, the clinical meaningfulness of testosterone in the management of sarcopenia should be carefully evaluated.…”