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Title: Mechanisms of androgen-induced hypertrophy : lessons from muscle cell models
Author: Hughes, David Conway
ISNI:       0000 0004 5353 8357
Awarding Body: University of Bedfordshire
Current Institution: University of Bedfordshire
Date of Award: 2014
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Androgen endocrine physiology is responsible for many processes in the body, from bone metabolism to skeletal muscle maintenance. Testosterone is one of the most potent androgens produced, with decades of research highlighting its androgenic-anabolic effect on skeletal muscle growth. The research has been further driven through the emergence of pharmaceutical derivates (steroids) of testosterone and their use in interventions for muscle wasting associated with disease and advancing age (sarcopenia). However, the molecular regulation of testosterone and the influence it has on cellular processes in promoting muscle development, hypertrophy and satellite cell activation (proliferation, differentiation) remain poorly understood. In summary, this thesis has highlighted the impact of testosterone in rescuing an aged phenotype in myoblast cells (PD cells) displaying prior reductions in regeneration and hypertrophy vs. relevant ‘un-aged’ controls (Sharples et al., 2011, Sharples et al., 2012). Importantly, the results provide evidence towards the mechanisms for testosterone induced hypertrophy, where in the presence of testosterone and a functional androgen receptor (shown via AR antagonism/ flutamide administration) testosterone is fundamental in regulating appropriate myoD, myogenin and myostatin expression in the control of myotube differentiation and hypertrophy. Increases in androgen receptor protein levels in PD myoblasts under a testosterone stimulus highlight the intrinsic responsiveness of aged myoblasts to a hypertrophic stimulus which may somewhat explain the use of testosterone as an effective clinical treatment in muscle wasting disease. Finally, myotube hypertrophy occurred in both aged and un-aged myoblasts with testosterone administration even in the presence of an IGF-I receptor inhibitor (Picropodophyllin) suggesting a limited role of the IGF-IR and associated signaling in testosterones mediated increases in differentiation and hypertrophy. Testosterone did appear however to increase Akt phosphorylation in cells that show a prior impaired regenerative capacity (PD cells), even in the presence-IGF-IR inhibitor suggesting that testosterone can directly activate Akt independently of upstream IGF-IR a novel finding that is presented in chapter 5. This interaction maybe mediated by myostatin, where increases in myostatin has been linked with directly inhibiting Akt (Dubois et al., 2014, Léger et al., 2008, Morissette et al., 2009), and in the present study we see an increase in myostatin mRNA and corresponding decrease in phospho-Akt when AR’s (via flutamide) action is inhibited and the protein level of AR is low (chapter 5). Furthermore in chapter 6 we further showed that inhibition of PI3K/AKT using LY294002 was sufficient to remove the prior rescuing of differentiation and hypertrophy in aged cells after testosterone administration. This was coupled with reductions in myostatin and increases in mTOR with testosterone administration. Overall AR seems to be the most fundamental pathway in testosterones induction of myotube differentiation and hypertrophy with important roles for myogenin, Akt, mTOR and myostatin in mediating these processes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: C130 Cell Biology ; hypertrophy ; muscle ; androgens