Mechanisms of Testosterone Effects on Body Composition
Principal Investigator: Shalendar Bhasin
Abstract: Testosterone supplementation increases muscle mass and decreases fat mass in healthy young men, hypogonadal men, and in HTV-infected men with weight loss; these observations have prompted clinical trials of testosterone supplementation in MTV-infected men with weight loss or fat redistribution syndromes. However, the molecular mechanisms by which testosterone regulates muscle and fat mass are unknown and are the objective of this investigation. We hypothesize that testosterone and dihydrotestosterone (DHT), two prototypical androgens, promote the differentiation of adult, pluripotent mesenchymal stem cells into myogenic lineage and inhibit the differentiation of these cells into adipogenic lineage through an androgen receptor pathway. These studies will determine whether testosterone and DHT promote myogenic commitment and inhibit adipogenic differentiation of mesenchymal, pluripotent cells by activation of Wnt signaling pathway. We will employ two validated in vitro models of adult, mesenchymal, stem cell commitment and differentiation, namely, adult, pluripotent stem cells isolated from lipoaspirates, and muscle stem cells isolated from regenerating skeletal muscle of adult mice after an injury. We will determine the effects of graded doses of testosterone and DHT on myogenic and adipogenic differentiation of adult, mesenchymal, stem cells in vitro, and evaluate whether the effects of testosterone are blocked by bicalutamide, an androgen receptor antagonist. Promyogenic effects of testosterone on differentiation and commitment of mesenchymal stem cells will be studied in a mouse model of muscle injury and regeneration. In this model, we will determine the effects of surgical orchiectomy without and with testosterone replacement on the number of mesenchymal precursor cells (CD34+, Pax7), satellite cells (CD34+, Pax7+, located inside the basal lamina), and number of donor cells fused with muscle fibers during regeneration following muscle injury. To demonstrate Wnt activation , we will first determine whether testosterone or DHT cause translocation of p-catenin into nucleus, a hallmark of Wnt activation, and decrease the amount of phosphorylated p-catenin. The interaction and co-localization of p-catenin and androgen receptor in the nucleus will be analyzed. We will evaluate whether inhibition of beta-catenin by a silencer RNA blocks the activation of TCF4 and MyoD transcription by testosterone and DHT. We will also assess whether testosterone and DHT induce TCF4 transcription, and upregulate Pax 7 and MyoD expression, while downregulating adipogenic differentiation markers, PPARgamma2 and C/EBPalpha. We will ascertain whether inhibition of TCF4 by a dominant negative TCF4 cDNA blocks upregulation of Pax 7 and MyoD and downregulation of PPARgamma2 and C/EBPa, by testosterone and DHT. These studies will provide novel insights into the mechanisms of androgen action on the skeletal muscle and have direct relevance to the proposed applications of testosterone for the treatment of HTV-associated weight loss and fat redistribution syndromes and for the development of selective androgen receptor modulators.
Funding Period: 2004-09-30 - 2008-06-30
more information: NIH RePORT
- Growth hormone in the aging maleFred R Sattler
Keck School of Medicine, University of Southern California, 2020 Zonal Avenue, IRD Building, Room 434, Los Angeles, CA 90033, USA Electronic address
Best Pract Res Clin Endocrinol Metab 27:541-55. 2013..This report critically reviews the potential for GH augmentation during aging with emphasis on men since women appear more resistant to treatment. ..
- Cardiometabolic risks during anabolic hormone supplementation in older menJ He
Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA
Obesity (Silver Spring) 21:968-75. 2013..To determine the cardiometabolic risks of testosterone and growth hormone (GH) replacement therapy to youthful levels during aging...
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Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, MA 02118, USA
J Gerontol A Biol Sci Med Sci 68:17-26. 2013..These data suggest prospective application of androgens to improve the regenerating potential of the aged human skeletal muscle...
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Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts, USA
J Am Geriatr Soc 56:1991-9. 2008..To examine the effect of graded doses of testosterone on physical function and muscle performance in healthy, older men...
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Division of Biokinesiology and PT, University of Southern California, 1540 East Alcazar St CHP 155, Los Angeles, CA 90033, USA
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Department of Medicine, Washington University, St Louis, MO, USA
Am J Clin Nutr 94:172-81. 2011..Acute deviations in protein intake before the quantification of protein kinetics in older humans may explain the controversy over the effects of older age on muscle protein synthesis and proteolysis rates...
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Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, 670 Albany Street, Boston, Massachusetts 02118, USA
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Section of Endocrinology, Diabetes, and Nutrition, Boston Claude D Pepper Older Americans Independence Center for Function Promoting Therapies, Boston University School of Medicine, Boston, Massachusetts, USA
Curr Opin Clin Nutr Metab Care 12:232-40. 2009..This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity...
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Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts 02199, USA
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Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, 670 Albany Street, Boston, MA 02118, United States
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Departments of Medicine, Division of Biokinesiology, Keck School of Medicine, University of Southern California, 1200 North State Street, Room 6442, Los Angeles, California 90033, USA
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Department of Medicine, Boston University, School of Medicine, Boston Medical Center, Boston, MA 02118, USA
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Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, 670 Albany Street, 2nd Floor, Boston, Massachusetts 02118, USA
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Division of Biokinesiology, University of Southern California, Los Angeles, CA 90033, USA
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Department of Medicine, Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts 02118, USA
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Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University, Los Angeles, CA 90059, USA
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Division of Endocrinology, Charles R Drew University of Medicine, Los Angeles, California 90059, USA
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