However, with the exception of a polymorphism in the AR gene (with the potential to affect testosterone levels) (Guilherme et al. 2021b), the interaction of testosterone-increasing alleles with muscle mass and function remains to be investigated. These innate characteristics may lead to interindividual differences in hormone levels capable of influencing testosterone-related phenotypes, such as predisposition to increase muscle mass and strength. The aim of the present study was to test the association of 822 testosterone-increasing SNPs with muscle-related traits (muscle fiber size, fat-free mass and handgrip strength) and to validate the identified SNPs in independent cohorts of strength and power athletes. The effects of androgens on skeletal muscle are very diverse and are mediated via different cellular targets as well as biochemical pathways, as summarized in Figs. Thus, androgen-mediated increase in skeletal muscle mass is, at least partly, mediated through activation of PI3K/Akt signaling, resulting in both stimulation of protein synthesis and inhibition of protein degradation (Fig. 3). In summary, the main cellular targets for androgens in skeletal muscle include satellite cells and myonuclei, but actions on pluripotent mesenchymal precursor cells and motoneurons may also contribute to the eventual outcome (Fig. 1). Although there is agreement that androgen administration increases muscle mass, data on the effects of testosterone supplementation on muscle performance and physical function are less clear. The large sample size of the NHANES dataset minimized non-sampling and measurement errors due to the rigorous study design and data-processing criteria. Studies have demonstrated that testosterone administration improves stair-climbing power, leg press power, and chest press strength and power (Storer et al., 2017). Second, type II fibers, critical for strength and power, exhibit more pronounced atrophy and decrease in number with age, while type I fibers are less affected (Lexell, 1995). Aging diminishes the number and function of alpha motor neurons, leading to fewer muscle fibers being activated during contraction. Androgen deprivation therapy (ADT), commonly used in prostate cancer treatment, has been shown to cause significant reductions in lean mass (Chang et al., 2014) and muscle cross-sectional areas (Storer et al., 2017). Smoking and drinking behavior not only affects testosterone levels, but also negatively impacts muscle health (Xia et al., 2024; Ko et al., 2020). In men, a positive linear relationship was found between testosterone and muscle mass but not muscle strength, suggesting a disconnect between muscle mass preservation and functional strength gains. Serum testosterone levels also decline by ∼110 ng/dL per decade in older adults (Morley et al., 1997), prompting interest in their interplay with muscle health. However, no significant association was observed between testosterone levels and GSMAX or low muscle strength in men. In men, no correlation was observed between testosterone levels and low muscle strength. Moreover, testosterone causes a significant up-regulation of AR expression in these neurons as well as an increase of the number and size of the motoneurons themselves 86, 87. In addition, immunohistochemical staining reveals that these motoneurons also express AR , hereby further suggesting that androgen anabolic action may be mediated via muscle innervation. In addition, co-culture experiments reveal that adipogenesis of mesenchymal progenitors is strongly inhibited by the presence of satellite cell-derived myofibers . However, a third ARKO model shows a decreased muscle cross-sectional area accompanied by reduced potential of voluntary running but without increased adiposity or obesity 73, 74. However, further evidence of testosterone action on satellite cell differentiation is contradictory 48, 53, 54, 60. Association between log2-transformed testosterone levels and ALMBMI in males according to the general characteristics. Stratified and interaction analyses were conducted to determine whether the association between testosterone levels and ALMBMI were consistent across several subgroups (Figure 3). This association was maintained when the testosterone levels were transformed into quartiles. Multivariate linear regression analyses of the association between serum testosterone levels and ALMBMI and GSMAX in male participants are shown in Table 2. In conclusion (Fig. 2), androgens induce AR binding to DNA, either directly to AREs, or indirectly by tethering via other transcription factors that bind to muscle-specific enhancers. Deletion of Dicer in embryonic skeletal muscle results in perinatal lethality and a decreased skeletal muscle mass accompanied by abnormal myofiber morphology , hereby illustrating the essential role of miRNAs in muscle development and function. Non-genomic androgen pathways may be another mechanism by which androgens act on skeletal muscle. Other AR-expressing cell types such as pluripotent mesenchymal precursor cells and motoneurons may, however, contribute to myogenic androgen action as well. Satellite cells and myonuclei are considered to be the main targets of androgen action in muscle.
