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​Conversely, in pre-menopausal women, total testosterone levels demonstrated ​no significant relationship​ with either lean mass or handgrip strength (Alexander et al., 2021). Furthermore, physiological testosterone levels exhibited a positive correlation with lean mass and an inverse association with fat mass in males (Mouser et al., 2016). First, women in our cohort had testosterone levels approximately 20-fold lower than men, which may be below the threshold required to exert anabolic effects on muscle tissue (Shin et al., 2021). The sex-specific differences in the relationship between testosterone levels and muscle health may be attributed to several biological and hormonal factors. Conversely, testosterone replacement therapy (TRT) has been found to improve muscle mass and strength in hypogonadal men.
Muscle CSA can be affected by numerous environmental factors, but it is also highly determined by genetic factors. Since fast-twitch fibers are required in high-energy movement tasks such as sprinting or weightlifting, their CSA is of vital importance for power athletes. Not surprisingly, testosterone is the most common form of doping in sport; however, it should be mentioned that due to the dynamic regulation of its endogenous production, testosterone concentrations may vary considerably within and among individuals. In addition, testosterone plays a clear role on several non-reproductive tissues, regardless of gender.
However, despite growing clinical interest in anabolic action of androgens, many research questions remain largely unresolved. Clinical studies complemented with animal models and in vitro cell cultures continue to enhance our understanding of these processes. From this point of view, Mst is an ideal target molecule, since β-catenin and TGF-β/SMAD signaling play essential roles in mediating testosterone effects on myogenic differentiation (see previous sections).
There is a strong heritability for serum testosterone, with genetic factors accounting for 40–70% of the variation in testosterone levels in men (Travison et al. 2014) and 65% in women (Hong et al. 2001). Other anabolic or anti-catabolic mechanisms have also been proposed (Dubois et al. 2012), all suggestive that testosterone plays an important role in muscle mass regulation. Therefore, therapeutic agents that could achieve anabolic effects on skeletal muscle without androgenic activities such as prostatic effects and virilization are of great clinical interest. As discussed in the previous sections, it is now well established that androgen administration increases muscular and lean body mass.
Intervention studies further highlight the impact of testosterone on muscle metabolism. Existing studies have documented inconsistent associations between testosterone and muscle outcomes. Muscle mass and strength decline with age, with strength deterioration occurring threefold faster than mass loss (Goodpaster et al., 2006). Restricted cubic splines (RCS) were used to test for linearity and further investigate the dose-response relationship between testosterone and ALMBMI in men, adjusting for confounding factors consistent with Model 3. Data on total energy, protein, carbohydrate, fiber, and fat intakes were collected through a 24-hour dietary recall interview. Several important covariates, such as genetic factors, inflammatory markers, detailed dietary data, and other hormone levels, were not included in the analysis due to ​data limitations​ in NHANES.
Chronic low-grade inflammation is common in older adults and can affect muscle health independently of testosterone levels (Degens, 2010). Our findings are based on a snapshot of data collected at a single point in time, which means that we cannot infer temporal relationships between testosterone levels and muscle health outcomes. These effects are dose-dependent, with higher testosterone levels correlating with greater improvements in muscle performance (Storer et al., 2003). Studies have shown that androgen receptor density and activity can differ between sexes, potentially explaining the disparate effects of testosterone on muscle health (Schuppe et al., 2017).
Men lose 3-5% of their muscle mass per decade, so optimising your muscle gain becomes more important as you get older. Testosterone works by increasing the protein synthesis, which is the process by which muscle fibres repair and regenerate after exercise-induced damage. Other hormones, such as estrogen, growth hormone, and insulin-like growth factor-1 (IGF-1), interact with testosterone and could influence muscle health. For example, certain genetic variants may affect muscle fiber type distribution, muscle protein synthesis, and androgen receptor sensitivity (Ahmetov et al., 2012).

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