Unraveling Androgen Action in Muscle: Genetic Tools Probing Cellular Mechanisms

Abstract

For the largest tissue in the body and with functions relevant to virtually every medical discipline (although central to none), muscle physiology is surprisingly neglected in medical research. Despite profound discoveries in subcellular muscle structure and function winning Nobel prize recognition, understanding the physiological regulation of muscle as a tissue remains a mostly unexplored territory with few reliable landmarks. Perhaps in a world in which research remains most strongly propelled by discipline-based quests for knowledge, muscle as an orphan lacking a disciplinary home with the necessity and priority to drive deeper discovery has, accordingly, been relatively overlooked. Among the most salient biological clues to regulation of muscle function is the gender dimorphism in muscle mass and strength appearing after puberty and attributable to dramatic differences in endogenous androgen exposure. Considering the nearly 30-fold increase in testosterone production experienced across male puberty, men’s larger and stronger muscles testify to marked androgen dependence, providing an opportunity for pharmaceutical exploitation over the 7 decades since testosterone started being used clinically. Yet exploitation for therapeutic benefit has progressed slowly, due in part to the pharmaceutical industry’s failed, and then abandoned, quest for a pure anabolic (i.e. nonandrogenic) steroid in the postwar decades, the golden age of steroid pharmacology. By contrast, unscrupulous illicit androgen abuse has flourished on the fact of increased muscle mass and strength, which sufficed without requiring explanation (1). Only since decades of denial that exogenous androgens enhanced muscular mass and strength in eugonadal men (2) was overturned by the studies of Bhasin et al. (3) in the mid-1990s have androgens been clearly acknowledged as having the most potent known anabolic and ergogenic effects on skeletal muscle, a fact reflected by androgens continuing to be the most widely abused class of drugs used in sports doping as well as the wider community for nonmedical purposes (4). Rigorous, placebocontrolled studies show testosterone has dose-response effects on muscle mass (fiber hypertrophy) and strength from below to well above the physiological range in both young (5) and older (6) men. Furthermore, high-quality clinical studies show androgens increase muscle mass in various chronic diseases such as HIV wasting (7), chronic obstructive pulmonary disease (8), chronic renal disease (9), and burns (10) and possibly the frailty, falls, and fractures that diminish quality of life during ageing (11). Yet despite proven increases in muscle mass in a few small studies, androgens are not in routine clinical use for these indications because of both limited evidence of sufficient functional benefits and risks of adverse off-target effects on cardiovascular disease and the liver (for 17-alkylated androgens) as well as prostate disease in men and virilization or hormone-dependent cancers in women. Further pharmaceutical development coupled with well-controlled clinical studies still appears to have great, untapped potential for androgens as adjunctive therapy for ageing and chronic disease states. By modern biochemical definition, androgens act by binding to the androgen receptor (AR), a ligand-dependent nuclear transcription factor (12). Yet androgen action is complex, involving prereceptor enzymatic activation and postreceptor coregulator mechanisms (13) as well as cell and tissue specificity within target organs. Although androgens are classically considered reproductive hormones, AR is expressed almost ubiquitously (14) including in nonreproductive target tissues like skeletal muscle. Prereceptor activation of androgen action involves either amplification of testosterone to the more potent androgen dihydrotestosterone (15) or diversification by aromatization to estradiol with effects mediated via the estrogen receptor (ER)and (16). An additional mechanism of androgen action, involving nongenomic actions without apparently requiring DNA binding, remains ill defined and of unknown physiological importance (17). The pharmaceutical goal of separating androgenic (reproductive system, somatic virilization) from the anabolic (enhancing muscle and bone growth and function) actions of androgens has been revived after invention of the first nonsteroidal andro-