Mechanisms Of Testosterones Effects On Body Composition

The prevalent view that testosterone produces muscle hypertrophy by increasing fractional muscle protein synthesis (46,83) is supported by several studies. However, as discussed below, recent observations suggest that increase in muscle protein synthesis probably occurs as a secondary event and may not be the sole or the primary mechanism by which testosterone induces muscle hypertrophy (84).

To determine whether testosterone-induced increase in muscle size results from muscle fiber hypertrophy or hyperplasia, muscle biopsies were obtained from the vastus lateralis in 39 healthy, young men before and after 20 wk of combined treatment with GnRH agonist and weekly injections of 25-, 50-, 125-, 300-, or 600-mg testosterone enanthate (84). Graded doses of testosterone administration were associated with a testosterone dose- and concentration-dependent increase in muscle fiber cross-sectional area (see Fig. 3). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35 and 0.44, p < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, p < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of testosterone enanthate weekly experienced significant increases from baseline in areas of type I (baseline vs 20 wks, 3176 ± 163 vs 4201 ± 163 |m2, p < 0.05 at 300-mg dose, and 3347 ± 253 vs 4984 ± 374 |m2, p = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4060 ± 401 vs 5526 ± 544 |m2, p = 0.03) fibers. The relative proportion of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of testosterone enanthate and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. These data demonstrate that increases in muscle volume in healthy eugonadal men rendered testosterone-deficient with a GnRH-analog and treated with graded doses of testosterone are associated with concentration-dependent increases in muscle fiber cross-sectional area and myonuclear number but not muscle fiber number. We conclude that the testosterone-induced increase in muscle volume results from muscle fiber hypertrophy. In our study, the myonuclear number increased in direct relation to the increase in muscle fiber diameter. Therefore, it is possible that muscle fiber hypertrophy and increase in myonuclear number were preceded by testosterone-induced increase in satellite cell number and their fusion with muscle fibers. The mechanisms by which testosterone might increase satellite cell number are not known. An increase in satellite cell number could occur by an increase in satellite cell replication, inhibition of satellite cell apoptosis, and/or increased differentiation of stem cells into the myogenic lineage. We do not know which of these processes is the site of regulation by testosterone. The hypothesis that testosterone promotes muscle fiber hypertrophy by increasing the number of satellite cells should be further tested. Because of the constraints inherent in obtaining multiple biopsy specimens in humans, the effects of testosterone on satellite cell replication and stem cell recruitment would be more conveniently studied in an animal model.

The molecular mechanisms, which mediate androgen-induced muscle hypertrophy, are not well understood. Urban et al. (83) proposed that testosterone stimulates the expression of IGF-I and downregulates IGF-binding protein-4 (IGFBP-4) in the muscle. Reciprocal changes in IGF-1 and its binding protein thus provide a potential mechanism for amplifying the anabolic signal.

It is also not clear whether the anabolic effects of pharmacological doses of testosterone are mediated through the androgen receptor. In vitro-binding studies (85) suggested that the maximum effects of testosterone should be manifest at serum testosterone levels of approx 300 ng/dL, i.e., levels that are at the lower end of the normal male range. Therefore, it is possible that the supraphysiological doses of androgen pro duce muscle hypertrophy through an androgen-receptor independent mechanism, such as through an antiglucocorticoid effect (86). We cannot exclude the possibility that some androgen effects may be mediated through nonclassical binding sites. Testosterone effects on the muscle are modulated by several other factors, such as genetic background, growth hormone secretory status (87), nutrition, exercise, cytokines, thyroid hormones, and glucocorticoids. Testosterone may also affect muscle function by its effects on neuromuscular transmission (88,89).

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