Investigating the neural mechanisms of androgen action in the regulation of the musculoskeletal system.

Lead Researcher Email Number Webpage
Associate Professor Rachel Davey r.davey@unimelb.edu.au +61 3 9496 5507 Personal web page

Project Details

Androgens are one of the few agents proven to have anabolic effects in both muscle and bone, however, they are not used widely as a therapy in men due to their side-affects and they cannot be used in women. There are exciting but still circumstantial data on the effect of androgens acting via neurons in the brain on musculoskeletal function and body composition. We have an extensive body of work in mice showing that androgens regulate muscle and bone by direct actions via the androgen receptor.  The aim of this study is to determine the contribution of androgens acting via the androgen receptor in neurons and specifically in the hypothalamus to regulate skeletal muscle mass and function; and bone cell metabolism. We will achieve this aim by determining the effect of deleting the AR only in neurons throughout development (neuron-ARKO) and specifically in the adult hypothalamus (hypothalamic-ARKO) on muscle and bone. Direct comparisons with our previously described global- and tissue-specific ARKO models in which the AR is deleted only in the specific cells and/or tissue of interest (ie. myoblasts, myofibres, osteoblasts) will allow us to establish the relative contribution of androgens acting via the AR in neurons to regulate the musculoskeletal system. Understanding the central actions of androgens will provide a new paradigm for the anabolic actions of androgens in muscle and bone. This knowledge will facilitate the design of alternative therapies for treating muscle wasting and osteoporosis, and as such has important health care implications for these common diseases.

Researchers

Collaborators

  • Dr Jane Seto and Professor Kathryn North, Murdoch Childrens Research Institute

Funding

  • Austin Medical Research Foundation Research Grant, "The action of sex hormones in the brain to control bone and muscle."

Research Outcomes

  • Davey RA and Grossmann M. Androgen receptor structure, function and biology: From bench to bedside. The Clinical Biochemist Reviews, 2016, 37(1):3-15.
  • How JMY, Wardak SA, Ameer SI, Davey RA, Sartor DM. Are blunted sympathoinhibitory responses in obesity-related hypertension due to defective peripheral or central signaling mechanisms? Journal of Physiology, 2014, 592(Pt 7): 1705-1720.
  • Russell PK, Clarke MV, Skinner JP, Pang TPS, Zajac JD, Davey RA. Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice. Journal of Molecular Endocrinology, 2012, 49(1): 1-10.
  • Pang TPS, Clarke MV, Ghasem-Zadeh A, Lee NKL, Davey RA*, MacLean* (Equal senior authors). A physiological role for androgen actions in the absence of androgen receptor DNA binding activity. Molecular and Cellular Endocrinology, 2012, 348: 189-197.
  • MacLean HE, Moore AJ, Sastra SA, Morris HA, Ghasem-Zadeh A, Rana K, Axell AM, Notini AJ, Handelsman DJ, Seeman E, Zajac JD, Davey RA.  “DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females”. Journal of Endocrinology  2010, 206, 93-103.
  • Notini AJ, Davey RA, McManus JF, Bate KL, Zajac JD. Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. Journal of Molecular Endocrinology 2005; 35(3):547-55.

Research Group

Molecular Endocrinology and Musculoskeletal Research Group


School Research Themes

Musculoskeletal



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Medicine and Radiology

Unit / Centre

Molecular Endocrinology and Musculoskeletal Research Group