The Influence of Androgen Receptors on Muscle Repair and Hypertrophy

Abstract

The mechanisms underlying inter‐individual variation in adaptation to exercise have yet to be fully elucidated. Recently, high responders to resistance training (RT) have demonstrated greater levels of androgen receptor (AR) content, and therefore AR may be a factor underlying the variation in the adaptive response to resistance exercise. Moreover, there has been inconclusive findings surrounding the impact of AR content in females as well as following damage. In the current study, twenty‐six healthy young men (n=13) and women (n=13) underwent an acute bout of damaging exercise consisting of 300 eccentric kicks, followed by 10 weeks of full‐body RT to investigate changes in AR content following acute muscle damage and following chronic resistance exercise. This was assessed in the context of the satellite cell response and during muscle repair and hypertrophy. Skeletal muscle biopsies from the vastus lateralis were taken at baseline, 48 hours post damage and 48 hours following the last bout of RT. RT‐qPCR and western blots were performed to quantify AR gene expression and protein content, respectively. An immunofluorescence staining protocol was optimized for the visualization of AR protein abundance. Results were considered in the context of the SC response and muscle hypertrophy data from the same cohort. AR content increased from baseline (30457 +/‐ 4399 a.u.) to post‐damage (66448 +/‐ 8083 a.u.) by 218% (p=0.005) and post RT (60889 +/‐ 6636 a.u.) by 199% (p=0.003). Those with the greatest increase in SC content post‐damage also had the greatest increase in AR content (p=0.01). Individuals with the greatest increase in leg‐lean mass following RT also had the greatest increase in AR content (p=0.05). Preliminary data from western blot analysis revealed that AR protein content post‐damage in males was correlated with activated SC number (MyoD+ cells) (p=0.01). We then aimed to investigate sex differences in the context of AR content since there is a paucity of work in females. Males (61550 +/‐ 10961 a.u.) had a 198% greater change in AR content than females (31104 +/‐ 7499 a.u) from baseline to post‐damage (p=0.03). Males also had a greater change in AR content (3.186 +/‐ 0.5443) than females (2.003 +/‐ 0.2625) post‐RT, relative to baseline. In males, those with greater relative gains in muscle fibre CSA (high responders), post‐RT, had a 373% greater change in AR content (64936 +/‐ 11783 a.u.) from baseline to post‐RT than low responders (17388 +/‐ 15438) (p = 0.03). Interestingly in females, those with greater relative gain in CSA post‐RT (1.681 +/‐ 0.4120) had a trend towards lower AR content post‐RT compared to low responders (2.502 +/‐ 0.1946) (p = 0.06). This study is the first to immunofluorescently stain AR content for visualization and quantification in skeletal muscle. Collectively, these findings suggest that AR content influences SC activity and exhibits sex differences following damage and chronic resistance exercise.

Total testosterone is not associated with muscle mass, function or exercise adaptations in pre-menopausal females

“…Conversely, female ARKO mice did not display any differences in muscle mass or strength compared to their wildtype controls (MacLean et al ., 2008), further demonstrating sex-specific differences in the role of the AR in the maintenance of muscle mass and function. We also confirm that resistance training does not affect AR protein content, phosphorylation status or nuclear localisation in female skeletal muscle, in agreement with previous work showing no change in AR protein content or nuclear localisation following 10 weeks of resistance training (n=13 females) (Hatt et al ., 2024). Males, in contrast, display significant increases in both AR protein content and nuclear localisation after the same resistance training program (Hatt et al ., 2024), suggesting further sex-specific AR regulation with chronic resistance exercise.…”

“…There is evidence of positive associations between endogenous total testosterone and muscle mass or strength in large male cohorts across the lifespan ( n =252 (Mouser et al ., 2016), n =3,875 (Ye et al ., 2021)). Other, smaller studies refute the existence of such an association ( n =49 (Morton et al ., 2018), n =23 (Mitchell et al ., 2013), n =67 (Mobley et al ., 2018), n =49 (Morton et al ., 2016)) and instead propose that increased skeletal muscle AR protein content (Morton et al ., 2018), or nAR (Hatt et al ., 2024), but not total or bioavailable circulating testosterone (Morton et al ., 2016; Morton et al ., 2018), is associated with increased muscle hypertrophy and function in young males.…”

“…Our knowledge of the association between endogenous testosterone and muscle mass is limited in females (Alexander et al ., 2022) and the available evidence stems from cross-sectional cohorts. Evidence from murine (Yoshioka et al ., 2007) and human (Pataky et al ., 2023; Hatt et al ., 2024) models however suggest that there are sex-specific differences in androgen action on the skeletal muscle transcriptome. We and others show that there is no association between endogenous total testosterone or nAR and muscle mass and strength in pre-(Alexander et al ., 2021; Hatt et al ., 2024) or post-menopausal females (Gower & Nyman, 2000; Carmina et al ., 2009; van Geel et al ., 2009; Pöllänen et al ., 2011; Rariy et al ., 2011; Kogure et al ., 2015).…”

“…Evidence from murine (Yoshioka et al ., 2007) and human (Pataky et al ., 2023; Hatt et al ., 2024) models however suggest that there are sex-specific differences in androgen action on the skeletal muscle transcriptome. We and others show that there is no association between endogenous total testosterone or nAR and muscle mass and strength in pre-(Alexander et al ., 2021; Hatt et al ., 2024) or post-menopausal females (Gower & Nyman, 2000; Carmina et al ., 2009; van Geel et al ., 2009; Pöllänen et al ., 2011; Rariy et al ., 2011; Kogure et al ., 2015). Instead, the free androgen index (FAI), which is indicative of the amount of bioavailable testosterone, is weakly associated with muscle mass in pre-menopausal females (Carmina et al ., 2009; Alexander et al ., 2021).…”