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The androgen hormone is responsible for the growth of secondary sex characteristics in humans, such as skeletal muscle. Upon an exercise stimulus, the androgen receptor (AR) plays a crucial role in transmitting the androgenic signal to the nucleus which upregulates transcription of target genes related to growth of skeletal muscle. AR content has been implicated in the hypertrophic response between high and low responders following resistance exercise training (RET) in males. Little is known of the impact of AR expression on acute skeletal muscle damage and whether AR may influence the adaptive response to RET in females. This study aimed to investigate acute changes to AR content following a single bout of muscle damage-inducing exercise as well as sex differences during skeletal muscle repair and hypertrophy. A skeletal muscle biopsy from the vastus lateralis was obtained from 26 healthy, young males (n=13) and females (n=13) at baseline and 48 hours following a single bout of 300 eccentric contractions of the quadriceps. Subsequently, participants performed whole-body RET 4 times a week for 10 weeks, followed by a final skeletal muscle biopsy under resting conditions. Females had greater AR mRNA than males at baseline (~53%) and post-damage (~126%; p<0.05) while AR protein content increased in both sexes similarly following a single bout of eccentric exercise (p<0.05). Damage- and RET-induced satellite cell response was associated with percent change in AR protein content in a sex-specific manner (p<0.05). RET-induced percent change in nuclear AR content was ~17% greater in males compared to females (p<0.05). Interestingly, following RET, males experiencing the highest percent change in myofibre cross sectional area (CSA) exhibited greater changes in nuclear-associated AR protein content compared to females with the highest percent change in CSA. Collectively, AR protein content is elevated following acute eccentric exercise and 10 weeks of RET. Findings from this study suggests that males are more reliant on AR-related mechanisms than females to induce skeletal muscle hypertrophy following RET. / Thesis / Master of Science in Kinesiology / Skeletal muscle is crucial for proper function and activities of daily living. Many factors can regulate the amount and quality of skeletal muscle such as the expression of a protein known as the androgen receptor (AR). The AR plays a role in many cellular pathways that can ultimately dictate the growth and size of a particular tissue like skeletal muscle. There is currently minimal research about AR during skeletal muscle damage and in female skeletal muscle. Understanding how exercise increases AR content in males and females could progress our knowledge of how muscle adapts differently to exercise between sexes. Therefore, the purpose of this study was to understand how the AR behaves in the muscle, in males and females, after a single session of exercise that damages the muscle or after long term resistance exercise (RE). We observed that the AR gene is more abundant in females than males at rest and following damaging exercise. Furthermore, we show that AR protein content increases in both sexes following a single session of damaging exercise and after chronic RE. Muscle stem cells are a component of the muscle that helps to heal muscle after exercise has been performed. In the current study, we demonstrate that AR has a closer relationship to muscle stem cells in males relative to females. Further, AR seems to be more closely linked to muscle growth in males than females. Altogether, AR is a component of the muscle that adapts to exercise differently in males and females. This study may, in part, explain how skeletal muscle responds differently between sexes after exercise.

Prostate cancer is the most common cancers in men. Androgen receptor (AR) is the primary driver of prostate cancer progression, and androgens are the male hormones to activate AR to simulate prostate cancer cells to grow. Thus, current therapy focuses on stopping androgen biosynthesis or blocking AR. However, suppression of AR activity by androgen depletion or direct AR antagonist treatment leads to emergence of castrate-resistant prostate cancer. Sigma-2 receptor (σ2R) plays an important role in cholesterol homeostasis and has been implicated in carcinogenesis including prostate cancer. Its molecular identity remained elusive until 2017 when transmembrane protein 97 (TMEM97) was identified as the bona fide sigma-2 receptor. Past studies have shown that σ2R is highly expressed in various mammalian tumor cell lines and TMEM97 was proposed as an oncogene in various cancers. We hypothesized that TMEM97/σ2 receptor regulates the expression and activities of androgen receptor and its variants to promote prostate cancer proliferation, and it can be a novel target of intervention to reduce AR oncogenic signaling in prostate cancer. The goal of this study is to define the role of TMEM97/σ2 receptor in prostate cancer, to unveil the mechanisms of TMEM97-AR interactions, and to explore therapeutic opportunity targeting TMEM97/σ2 receptor.Here we demonstrated that elevated TMEM97/σ2 receptor was found in prostate tumors of higher malignancy and advanced stages, and was associated with reduced survival of prostate cancer patients. Increased expression of TMEM97 enhanced prostate cancer cell proliferation, clonogenicity, and enzalutamide resistance. Knockdown of σ2 receptor expression reduced prostate cancer cell growth and clonogenicity, and sensitized LNCaP and castration resistant 22Rv1 cells towards enzalutamide. There was a positive correlation between TMEM97 and AR expressions in prostate cancers. Sigma-2 receptor knockdown reduced the protein expression of AR and its AR-V7 variant under hormone deprivation condition. Decreased TMEM97 also downregulated AR activities by inhibiting expression of prostate cancer maker genes and AR target genes. Its physical interaction with sigma-1 receptor was noticed, which may contribute to the regulation of AR. Sigma-2 receptor agonist can stimulate AR target genes expressions while antagonist decreased them. In addition, sigma-2 receptor antagonist provided synergism with enzalutamide treatment, showing therapeutic potential to overcome the resistance to current AR-targeted therapies.

Androgens are critical for the development and maintenance of adult male characteristics such as muscle mass and sexual function. Consequently, the established decline with age of serum testosterone (T) in males has major health implications. While the androgen receptor (AR) is the major mediator of genomic androgen action and is required for the development of the male phenotype, reproductive organs and the maintenance of male secondary sexual characteristics, it is the entrance of androgens into the cell that mediates the activation of the AR and the subsequent modulation of expression of androgen regulated genes. Testosterone, biologically the most important androgen in male serum, circulates either free, loosely bound to albumin or tightly bound to sex hormone binding globulin (SHBG). Each of these forms of serum T have different abilities to enter cells, and which proportion of serum T is capable of entering cells and initiating the androgen signalling cascade, thereby leading to the activation of the AR has not been precisely defined. The AR amino terminal domain (NTD) is responsible for the majority of the ability of the AR to activate genes but the relative roles of the two activation functions in the AR NTD (activation functions 1 and 5; AF1 and 5) have not been precisely defined while the role of the AF2 surface which forms in the ligand binding domain upon agonist binding is responsible for interactions with key coregulators and also with the NTD in the amino-carboxyl (N/C) interaction. Our laboratory has recently identified a region within AF5 between amino acids 500-535 to which somatic mutations in castrate resistant prostate tumour samples collocate. Due to the lack of functional information on the AF5 region and the NTD in general, the function of this region and the functional consequences of the mutations remain to be defined. The objectives of this thesis were to develop a specific mammalian cell based bioassay capable of reliable measuring T in serum and to determine the ability of this bioassay to measure a physiologically relevant fraction of T in serum. Additionally, this thesis aimed to determine the relative contributions and roles of the activation functions of the AR to overall AR transcriptional activity along with the functional consequences for AR signalling of prostate cancer mutations which have previously been identified in the AF5 region of the AR NTD. The mammalian-cell based bioassay developed in this thesis is capable of sensitively and reliably measuring serum T. However, evaluation of this bioassay utilising approximately 1000 serum samples from the Florey Adelaide Male Aging Study reveals that this bioassay measures a fraction of T in serum that most closely relates to serum T. Furthermore, this measure does not correlate more strongly with grip strength, sexual function or waist circumference than the existing immunoassay-based measures of serum T, highlighting the limitations of utilising a static mammalian cell-based androgen bioassay to measure physiological levels of serum T in males. The investigation of the roles of the activation functions in the AR in this thesis have revealed that while the AF1 domain is responsible for the majority of the transactivation activity of the AR, AF5 and AF2 govern the sensitivity and cellular response of the AR to androgens by providing protein and interdomain interaction interfaces. Furthermore, the evidence in this thesis demonstrates that the AR requires interdomain communication for sensitive AR signalling. Finally, the findings in this thesis demonstrate that the AF5 surface is required for the N/C interaction and coregulator interactions while advanced prostate cancer mutations identified within this region confer increased transactivation activity of the AR in the presence of high cellular levels of coregulators. Collectively, the findings in this thesis provide several novel insights into the mechanism of action of serum androgens and challenges several long held assumptions of androgenic action in males. These findings also delineate a mechanism of treatment failure in advanced prostate cancer, provide a novel model for the events leading to sensitive AR transactivation and contribute to the understanding of physiologically relevant levels of serum T. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Although androgens are known to exert anabolic effects in skeletal muscle, overexpression of androgen receptor (AR) selectively in this tissue causes androgen dependent motor deficits and muscular atrophy. The cellular and subcellular changes underlying this phenotype are unknown. Therefore, this study aimed to elucidate the ultrastructural and histologic changes accompanying myopathy and to determine the importance of androgens and overexpression level for myopathic features. Transmission electron microscopy revealed augmented mitochondrial content and reduced myofibril width in androgen exposed transgenics. Additionally, male transgenics demonstrated increased glycogen content. Histochemical analyses confirmed sex-specific changes in glycogen content and revealed a surprising loss in the proportion of oxidative fibers in symptomatic animals. However, increased mitochondrial content was confirmed by the presence of ragged red fibers. Overexpression of AR in muscle fiber results in mitochondrial pathology and dysregulation of glycogen metabolism, possibly reflecting normal but exaggerated function of androgens in skeletal muscle fibers.

Although androgens are known to exert anabolic effects in skeletal muscle, overexpression of androgen receptor (AR) selectively in this tissue causes androgen dependent motor deficits and muscular atrophy. The cellular and subcellular changes underlying this phenotype are unknown. Therefore, this study aimed to elucidate the ultrastructural and histologic changes accompanying myopathy and to determine the importance of androgens and overexpression level for myopathic features. Transmission electron microscopy revealed augmented mitochondrial content and reduced myofibril width in androgen exposed transgenics. Additionally, male transgenics demonstrated increased glycogen content. Histochemical analyses confirmed sex-specific changes in glycogen content and revealed a surprising loss in the proportion of oxidative fibers in symptomatic animals. However, increased mitochondrial content was confirmed by the presence of ragged red fibers. Overexpression of AR in muscle fiber results in mitochondrial pathology and dysregulation of glycogen metabolism, possibly reflecting normal but exaggerated function of androgens in skeletal muscle fibers.

abstract: Efforts to treat prostate cancer have seen an uptick, as the world’s most commoncancer in men continues to have increasing global incidence. Clinically, metastatic prostate cancer is most commonly treated with hormonal therapy. The idea behind hormonal therapy is to reduce androgen production, which prostate cancer cells require for growth. Recently, the exploration of the synergistic effects of the drugs used in hormonal therapy has begun. The aim was to build off of these recent advancements and further refine the synergistic drug model. The advancements I implement come by addressing biological shortcomings and improving the model’s internal mechanistic structure. The drug families being modeled, anti-androgens, and gonadotropin-releasing hormone analogs, interact with androgen production in a way that is not completely understood in the scientific community. Thus the models representing the drugs show progress through their ability to capture their effect on serum androgen. Prostate-specific antigen is the primary biomarker for prostate cancer and is generally how population models on the subject are validated. Fitting the model to clinical data and comparing it to other clinical models through the ability to fit and forecast prostate-specific antigen and serum androgen is how this improved model achieves validation. The improved model results further suggest that the drugs’ dynamics should be considered in adaptive therapy for prostate cancer. / Dissertation/Thesis / Masters Thesis Mathematics 2020

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