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

Gharahdaghi, Nima; Rudrappa, Supreeth; Brook, Matthew S.; Idris, Iskandar; Crossland, Hannah; Hamrock, Claire; Aziz, Hariz; Kadi, Fawzi; Tarum, Janelle; Greenhaff, Paul L.; Constantin‐Teodosiu, Dumitru; Cegielski, Jessica; Phillips, Bethan E.; Wilkinson, Daniel J.; Szewczyk, Nathaniel J.; Smith, Kenneth; Atherton, Philip J.

Authors

Supreeth Rudrappa

Matthew S. Brook

ISKANDAR IDRIS Iskandar.Idris@nottingham.ac.uk
Clinical Associate Professor & Honoraryconsultant Physician

Hannah Crossland

Claire Hamrock

Hariz Aziz

Fawzi Kadi

Janelle Tarum

Dumitru Constantin‐Teodosiu

Bethan E. Phillips

Nathaniel J. Szewczyk

KENNETH SMITH KEN.SMITH@NOTTINGHAM.AC.UK
Professor of Metabolic Mass Spectrometry

PHILIP ATHERTON philip.atherton@nottingham.ac.uk
Professor of Clinical, metabolic & Molecular Physiology



Abstract

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 less than 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 less than 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.

Citation

Gharahdaghi, N., Rudrappa, S., Brook, M. S., Idris, I., Crossland, H., Hamrock, C., …Atherton, P. J. (2019). Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men. Journal of Cachexia, Sarcopenia and Muscle, 10(6), 1276-1294. https://doi.org/10.1002/jcsm.12472

Journal Article Type Article
Acceptance Date Jun 12, 2019
Online Publication Date Sep 30, 2019
Publication Date 2019-12
Deposit Date Aug 21, 2019
Publicly Available Date Aug 21, 2019
Journal Journal of Cachexia, Sarcopenia and Muscle
Print ISSN 2190-5991
Electronic ISSN 2190-6009
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 10
Issue 6
Pages 1276-1294
DOI https://doi.org/10.1002/jcsm.12472
Keywords Physiology (medical); Orthopedics and Sports Medicine
Public URL https://nottingham-repository.worktribe.com/output/2454370
Publisher URL https://onlinelibrary.wiley.com/doi/10.1002/jcsm.12472

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