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Submitted on June 12, 2003
Accepted on July 14, 2003
1 Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059
* To whom correspondence should be addressed. E-mail: sbhasin{at}ucla.edu.
Testosterone (T) supplementation increases skeletal muscle mass and decreases fat mass; however, the underlying mechanisms are unknown. We hypothesized that T regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage. Mouse C3H 10T1/2 pluripotent cells were treated with T (0-300 nM) or dihydrotestosterone (DHT, 0-30 nM) for 0-14 days, and myogenic conversion was evaluated by immunochemical staining for early (MyoD) and late (myosin heavy chain II: MHC) myogenic markers, and measurements of MyoD and MHC mRNA and protein. Adipogenic differentiation was assessed by adipocyte counting, and by measurements of PPAR
2 mRNA, and PPAR2 and C/EBP
proteins. The number of MyoD+ myogenic cells and MHC+ myotubes, and MyoD and MHC mRNA and protein levels increased dose-dependently in response to T and DHT treatment. Both T and DHT decreased the number of adipocytes and downregulated the expression of PPAR2 mRNA and PPAR2 and C/EBP proteins. Androgen receptor (AR) mRNA and protein levels were low at baseline, but increased after T or DHT treatment. The effects of T and DHT on myogenesis and adipogenesis were blocked by bicalutamide. Hence, T and DHT regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an AR-mediated pathway. The observation that differentiation of pluripotent cells is androgen-dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men.
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