N

T3 40 ip 30 20

T3 40 ip 30 20

0 3 30 100 300 Testosterone (nM)

0 3 30 100 300 Testosterone (nM)

C 0 1 3 10 30 : DHT (nM) PPAR-y . SJt -- . . ^52 kD

42 kD 30 kD

C/EBPa

Fig. 8.4 Effects of testosterone supplementation on myogenic and adipogenic differentiation in C3H10T1/2 pluripotent cells. Panel A shows immunocytochemical staining of MHC+ myogenic cells. 10T1/2 cells, treated for 12 days with testosterone (0 to 300 nM) or DHT (0 to 30 nM, not shown), were analyzed by immunocytochemistry using an anti-MHC antibody. Negative control did not include the first antibody (w/o 1st ab). Total areas of MHC+ cells per field are plotted in the lower panel. P vs. control: **, <0.01; ***, <0.001. Magnification 100X. Panel B shows the effect of testosterone or DHT on adipocyte number. 10T1/2 cells were grown with increasing doses of testosterone or DHT for 12 days. The average number of adipocytes was calculated for each 100X field. P vs. control: *, =0.02; **, P < 0.004; ***, P < 0.001. Panel C shows the effect of DHT on PPAR72 and C/EBPa protein expression. Cell extracts were analyzed by immunoblotting using anti-PPAR^, anti-C/EBPa or anti-GAPDH antibody. DHT concentrations (nM) and protein sizes (kD) are shown. (Adapted with permission from Singh etal. 2003.)

Fig. 8.5 A schematic representation of the hypothetical sites in pluripotent stem cell differentiation at which testosterone might act to affect body composition

Testosterone has been shown to stimulate mesenchymal pluripotent cell commitment into the myogenic lineage and inhibit the differentiation of these cells into the adipogenic lineage. In addition, testosterone has been reported to stimulate satellite cell replication and inhibit differentiation of preadipocytes into adipocytes. Thus, testosterone action at multiple sites in this cascade might serve to amplify androgen effects on myogenesis and adipoge-nesis. Testosterone supplementation also stimulates muscle protein synthesis and inhibits muscle protein degradation; these actions could also contribute to muscle fiber hypertrophy (Reproduced with permission from Bhasin etal. 2003).

Fig. 8.5 A schematic representation of the hypothetical sites in pluripotent stem cell differentiation at which testosterone might act to affect body composition

Testosterone has been shown to stimulate mesenchymal pluripotent cell commitment into the myogenic lineage and inhibit the differentiation of these cells into the adipogenic lineage. In addition, testosterone has been reported to stimulate satellite cell replication and inhibit differentiation of preadipocytes into adipocytes. Thus, testosterone action at multiple sites in this cascade might serve to amplify androgen effects on myogenesis and adipoge-nesis. Testosterone supplementation also stimulates muscle protein synthesis and inhibits muscle protein degradation; these actions could also contribute to muscle fiber hypertrophy (Reproduced with permission from Bhasin etal. 2003).

unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men. It is possible that androgens might also have effects on additional steps in the myogenic and adipogenic differentiation pathways (Fig. 8.5).

The molecular mechanisms which mediate androgen-induced muscle hypertrophy are not well understood. Urban et al. (1995) have proposed that testosterone stimulates the expression of insulin-like growth factor-I (IGF-I) and downregulates insulin-like growth factor 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 not clear whether the anabolic effects of supraphysiologic doses of testosterone are mediated through an androgen receptor-mediated mechanism. in vitro binding studies (Wilson 1988) suggest that the maximum effects of testosterone should be manifest at about 300 ng/dL, i.e., serum testosterone levels that are at the lower end of the normal male range. Therefore, it is possible that the supraphysiologic doses of androgen produce muscle hypertrophy through androgen-receptor independent mechanisms, such as through an anti-gluco-corticoid effect (Konagaya and Max 1986). We cannot exclude the possibility that some androgen effects maybe mediated through non-classical binding sites. Testosterone effects on the muscle are modulated by a number of other factors such as the genetic background, growth hormone secretory status (Fryburg etal. 1997), nutrition, exercise, cytokines, thyroid hormones, and glucocorticoids. Testosterone may also affect muscle function by its effects on neuromuscular transmission (Blanco etal. 1997; Leslie etal. 1991).

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