Androgen action via the androgen receptor in neurons within the brain positively regulates muscle mass in male mice

Rachel A. Davey, Michele V. Clarke, Patricia K. Russell, Kesha Rana, Jane Seto, Kelly N. Roeszler, Jackie M.Y. How, Ling Yeong Chia, Kathryn North, Jeffrey D. Zajac

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Although it is well established that exogenous androgens have anabolic effects on skeletal muscle mass in humans and mice, data from muscle-specific androgen receptor (AR) knockout (ARKO) mice indicate that myocytic expression of the AR is dispensable for hind-limb muscle mass accrual in males. To identify possible indirect actions of androgens via the AR in neurons to regulate muscle, we generated neuron-ARKO mice in which the dominant DNAbinding-dependent actions of the AR are deleted in neurons of the cortex, forebrain, hypothalamus, and olfactory bulb. Serum testosterone and luteinizing hormone levels were elevated twofold in neuron-ARKO males compared with wild-Type littermates due to disruption of negative feedback to the hypothalamic-pituitarygonadal axis. Despite this increase in serum testosterone levels, which was expected to increase muscle mass, the mass of the mixed-fiber gastrocnemius (Gast) and the fast-Twitch fiber extensor digitorum longus hind-limb muscles was decreased by 10% in neuron-ARKOs at 12 weeks of age, whereas muscle strength and fatigue of the Gast were unaffected. The mass of the soleus muscle, however, which consists of a high proportion of slow-Twitch fibers, was unaffected in neuron-ARKOs, demonstrating a stimulatory action of androgens via the AR in neurons to increase the mass of fast-Twitch hind-limb muscles. Furthermore, neuron-ARKOs displayed reductions in voluntary and involuntary physical activity by up to 60%. These data provide evidence for a role of androgens via the AR in neurons to positively regulate fast-Twitch hind-limb muscle mass and physical activity in male mice.

Original languageEnglish
Pages (from-to)3684-3695
Number of pages12
JournalEndocrinology
Volume158
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017
Externally publishedYes

Cite this

Davey, R. A., Clarke, M. V., Russell, P. K., Rana, K., Seto, J., Roeszler, K. N., ... Zajac, J. D. (2017). Androgen action via the androgen receptor in neurons within the brain positively regulates muscle mass in male mice. Endocrinology, 158(10), 3684-3695. https://doi.org/10.1210/en.2017-00470
Davey, Rachel A. ; Clarke, Michele V. ; Russell, Patricia K. ; Rana, Kesha ; Seto, Jane ; Roeszler, Kelly N. ; How, Jackie M.Y. ; Chia, Ling Yeong ; North, Kathryn ; Zajac, Jeffrey D. / Androgen action via the androgen receptor in neurons within the brain positively regulates muscle mass in male mice. In: Endocrinology. 2017 ; Vol. 158, No. 10. pp. 3684-3695.
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abstract = "Although it is well established that exogenous androgens have anabolic effects on skeletal muscle mass in humans and mice, data from muscle-specific androgen receptor (AR) knockout (ARKO) mice indicate that myocytic expression of the AR is dispensable for hind-limb muscle mass accrual in males. To identify possible indirect actions of androgens via the AR in neurons to regulate muscle, we generated neuron-ARKO mice in which the dominant DNAbinding-dependent actions of the AR are deleted in neurons of the cortex, forebrain, hypothalamus, and olfactory bulb. Serum testosterone and luteinizing hormone levels were elevated twofold in neuron-ARKO males compared with wild-Type littermates due to disruption of negative feedback to the hypothalamic-pituitarygonadal axis. Despite this increase in serum testosterone levels, which was expected to increase muscle mass, the mass of the mixed-fiber gastrocnemius (Gast) and the fast-Twitch fiber extensor digitorum longus hind-limb muscles was decreased by 10{\%} in neuron-ARKOs at 12 weeks of age, whereas muscle strength and fatigue of the Gast were unaffected. The mass of the soleus muscle, however, which consists of a high proportion of slow-Twitch fibers, was unaffected in neuron-ARKOs, demonstrating a stimulatory action of androgens via the AR in neurons to increase the mass of fast-Twitch hind-limb muscles. Furthermore, neuron-ARKOs displayed reductions in voluntary and involuntary physical activity by up to 60{\%}. These data provide evidence for a role of androgens via the AR in neurons to positively regulate fast-Twitch hind-limb muscle mass and physical activity in male mice.",
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Davey, RA, Clarke, MV, Russell, PK, Rana, K, Seto, J, Roeszler, KN, How, JMY, Chia, LY, North, K & Zajac, JD 2017, 'Androgen action via the androgen receptor in neurons within the brain positively regulates muscle mass in male mice' Endocrinology, vol. 158, no. 10, pp. 3684-3695. https://doi.org/10.1210/en.2017-00470

Androgen action via the androgen receptor in neurons within the brain positively regulates muscle mass in male mice. / Davey, Rachel A.; Clarke, Michele V.; Russell, Patricia K.; Rana, Kesha; Seto, Jane; Roeszler, Kelly N.; How, Jackie M.Y.; Chia, Ling Yeong; North, Kathryn; Zajac, Jeffrey D.

In: Endocrinology, Vol. 158, No. 10, 01.10.2017, p. 3684-3695.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Davey, Rachel A.

AU - Clarke, Michele V.

AU - Russell, Patricia K.

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AU - Roeszler, Kelly N.

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AU - Zajac, Jeffrey D.

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