Testosterone (T) administration increases muscle mass and decreases fat mass in men. We have previously reported that T stimulates myogenic differentiation in mesenchymal multipotent C3H10T1/2 (10T1/2) cells through an androgen receptor (AR)-mediated pathway though interaction with β-catenin/TCF4 signaling. We found that an overexpression of full-length TCF4 led to an increase in MyoD and MHC II and follistatin (Fst) expression.
Objectives To investigate (1) if the T-supplementation leads to Fst up-regulation in vivo and (2) if Fst-knockdown abrogates the myogenic effects in an in vitro differentiation model.
Methods and Results In vivo: Castrated C57BL6J mice were sham treated and subcutaneously implanted with physiologic (1 cm) and supraphysiologic (2 cm) doses of T for 6 weeks. Body composition analysis was performed by DEXA scanning. Consistent with previous reports, castration resulted in decreased fat-free mass, total body weight, and weight of androgen-responsive levator ani (LA) muscle. In LA muscle, castration led to a decrease in Fst mRNA levels, which were restored by T supplementation in a dose-dependent manner. In vitro: To investigate the role of Fst in mediating myogenic effects of T treatment, incubation of 10T1/2 with recombinant Fst (0.4 μg/mL) led to a significant increase in key myogenic markers MyoD and MHC II (protein and mRNA) in the absence of T. In addition, treatment of these cells with anti-Fst antibody (1 μg/mL) and Fst siRNA abolished T-induced increase in MyoD and MHC II protein levels. Combined with in vivo data, in vitro our studies suggest that a T-induced increase in muscle mass may be mediated via induction of Fst.
Conclusions Fst plays major role during T-induced in vitro and in vitro changes in muscle mass. As Fst in known to bind and antagonize myostatin (Mst), the most potent inhibitor of muscle mass, we believe that T levels may regulate endogenous Fst/Mst interaction and thereby regulate body composition. As the promyogenic effects of T are achieved with a concomitant increased risk of elevated prostate-specific antigen (PSA), we posit that the use of Fst with a low dose of T may have therapeutic implications similar to those achieved with high levels of T supplementation.
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