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60 TESTOSTERONE REGULATION OF MUSCLE MASS: IN VITRO AND IN VIVO ROLE OF FOLLISTATIN.
  1. R. Singh1,
  2. M. Braga1,
  3. S. K. Sinha1,
  4. R. Miki1,
  5. S. Bhasin1,2,
  6. R. B. Tripathi1,
  7. R. Jasuja1,2
  1. 1Division of Endocrinology and RCMI Molecular Medicine Core at Charles R. Drew University, Los Angeles, CA
  2. 2Division of Endocrinology, Boston University, Boston, MA.

Abstract

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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