Mechanisms of Testosterone Effects on Body Composition

Summary

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

Top Publications

  1. pmc Growth hormone in the aging male
    Fred 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
  2. pmc Cardiometabolic risks during anabolic hormone supplementation in older men
    J He
    Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA
    Obesity (Silver Spring) 21:968-75. 2013
  3. pmc Testosterone improves the regeneration of old and young mouse skeletal muscle
    Carlo Serra
    Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, MA 02118, USA
    J Gerontol A Biol Sci Med Sci 68:17-26. 2013
  4. pmc Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men
    Thomas W Storer
    Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts, USA
    J Am Geriatr Soc 56:1991-9. 2008
  5. pmc Value of measuring muscle performance to assess changes in lean mass with testosterone and growth hormone supplementation
    E Todd Schroeder
    Division of Biokinesiology and PT, University of Southern California, 1540 East Alcazar St CHP 155, Los Angeles, CA 90033, USA
    Eur J Appl Physiol 112:1123-31. 2012
  6. pmc Whole-body and muscle protein metabolism are not affected by acute deviations from habitual protein intake in older men: the Hormonal Regulators of Muscle and Metabolism in Aging (HORMA) Study
    Kevin E Yarasheski
    Department of Medicine, Washington University, St Louis, MO, USA
    Am J Clin Nutr 94:172-81. 2011
  7. pmc The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle
    Carlo Serra
    Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, 670 Albany Street, Boston, Massachusetts 02118, USA
    Endocrinology 152:193-206. 2011
  8. pmc Selective androgen receptor modulators as function promoting therapies
    Shalender Bhasin
    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
  9. pmc Kinetic and thermodynamic characterization of dihydrotestosterone-induced conformational perturbations in androgen receptor ligand-binding domain
    Ravi Jasuja
    Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts 02199, USA
    Mol Endocrinol 23:1231-41. 2009
  10. ncbi Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration
    Kishore M Lakshman
    Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, 670 Albany Street, Boston, MA 02118, United States
    Mol Cell Endocrinol 302:26-32. 2009

Scientific Experts

  • Todd E Schroeder
  • Shalendar Bhasin
  • Carlo Serra
  • Kevin E Yarasheski
  • Fred Sattler
  • Andrea Coviello
  • Ravi Jasuja
  • J He
  • Kishore M Lakshman
  • Vandana Gupta
  • Thomas W Storer
  • Indrani Sinha-Hikim
  • R Roubenoff
  • S P Azen
  • E F Binder
  • C P Chou
  • C Castaneda-Sceppa
  • Katie St Ledger
  • Lisa A Collins-Racie
  • Michael E Burczynski
  • Andrew J Dorner
  • S Bradley Forlow
  • Christopher Corcoran
  • Edward R LaVallie
  • Lioudmila Tchistiakova
  • Lynne Magliano
  • Pratibha Chauhan
  • James L Kirkland
  • Wen Guo
  • Nathan K Lebrasseur
  • Rika Miki
  • Tamara Tchkonia
  • Jeanne Dzekov
  • Connie Dzekov
  • Jason C Viereck
  • Atam B Singh
  • Karen Choong
  • Linda Woodhouse
  • James A Hamilton
  • John N Flanagan
  • Rajan Singh
  • Navjot S Narula
  • Martin L Lee
  • Marcia Cornford
  • Hilda Gaytan

Detail Information

Publications17

  1. pmc Growth hormone in the aging male
    Fred 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. ..
  2. pmc Cardiometabolic risks during anabolic hormone supplementation in older men
    J 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...
  3. pmc Testosterone improves the regeneration of old and young mouse skeletal muscle
    Carlo Serra
    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...
  4. pmc Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men
    Thomas W Storer
    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...
  5. pmc Value of measuring muscle performance to assess changes in lean mass with testosterone and growth hormone supplementation
    E Todd Schroeder
    Division of Biokinesiology and PT, University of Southern California, 1540 East Alcazar St CHP 155, Los Angeles, CA 90033, USA
    Eur J Appl Physiol 112:1123-31. 2012
    ..001). Despite sizeable increases in LM measurements at week 8, tests of muscle performance did not show substantive improvements at this time point...
  6. pmc Whole-body and muscle protein metabolism are not affected by acute deviations from habitual protein intake in older men: the Hormonal Regulators of Muscle and Metabolism in Aging (HORMA) Study
    Kevin E Yarasheski
    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...
  7. pmc The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle
    Carlo Serra
    Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, 670 Albany Street, Boston, Massachusetts 02118, USA
    Endocrinology 152:193-206. 2011
    ..However, IGF-IR signaling in skeletal muscle fibers does not appear to be obligatory for mediating the anabolic effects of T on the mass of androgen-responsive skeletal muscles in mice...
  8. pmc Selective androgen receptor modulators as function promoting therapies
    Shalender Bhasin
    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...
  9. pmc Kinetic and thermodynamic characterization of dihydrotestosterone-induced conformational perturbations in androgen receptor ligand-binding domain
    Ravi Jasuja
    Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts 02199, USA
    Mol Endocrinol 23:1231-41. 2009
    ..DHT binding to AR-LBD involves biphasic receptor rearrangement including population of a molten globule-like intermediate state...
  10. ncbi Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration
    Kishore M Lakshman
    Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, 670 Albany Street, Boston, MA 02118, United States
    Mol Cell Endocrinol 302:26-32. 2009
    ..Myostatin levels were not significantly associated with lean body mass in either young or older men...
  11. pmc Testosterone and growth hormone improve body composition and muscle performance in older men
    Fred R Sattler
    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
    J Clin Endocrinol Metab 94:1991-2001. 2009
    ..Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat...
  12. pmc Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes
    Vandana Gupta
    Department of Medicine, Boston University, School of Medicine, Boston Medical Center, Boston, MA 02118, USA
    Mol Cell Endocrinol 296:32-40. 2008
    ..DHT stimulated forskolin-stimulated lipolysis in subcutaneous and mesenteric preadipocytes and inhibited incorporation of fatty acid into triglyceride in adipocytes differentiated from preadipocytes from all fat depots...
  13. pmc Effects of graded doses of testosterone on erythropoiesis in healthy young and older men
    Andrea D Coviello
    Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, 670 Albany Street, 2nd Floor, Boston, Massachusetts 02118, USA
    J Clin Endocrinol Metab 93:914-9. 2008
    ..Erythrocytosis is a dose-limiting adverse effect of testosterone therapy, especially in older men...
  14. ncbi Hormonal regulators of muscle and metabolism in aging (HORMA): design and conduct of a complex, double masked multicenter trial
    E Todd Schroeder
    Division of Biokinesiology, University of Southern California, Los Angeles, CA 90033, USA
    Clin Trials 4:560-71. 2007
    ..This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging...
  15. ncbi Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone
    Andrea D Coviello
    Department of Medicine, Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Clin Endocrinol Metab 91:4669-75. 2006
    ..We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels...
  16. ncbi Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men
    Indrani Sinha-Hikim
    Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University, Los Angeles, CA 90059, USA
    J Clin Endocrinol Metab 91:3024-33. 2006
    ..In this study, we determined the effects of graded doses of testosterone on muscle fiber cross-sectional area (CSA) and satellite cell number and replication in older men...
  17. ncbi Tetrahydrogestrinone is an androgenic steroid that stimulates androgen receptor-mediated, myogenic differentiation in C3H10T1/2 multipotent mesenchymal cells and promotes muscle accretion in orchidectomized male rats
    R Jasuja
    Division of Endocrinology, Charles R Drew University of Medicine, Los Angeles, California 90059, USA
    Endocrinology 146:4472-8. 2005
    ..This mechanism-based approach should be useful for rapid screening of anabolic/androgenic agents...