Low testosterone (T) in men, especially its free fraction, has been associated with loss of energy. In accordance, orchidectomy (ORX) in rodents results in decreased physical activity. Still, the mechanisms through which T stimulates activity remain mostly obscure. Here, we studied voluntary wheel running behavior in three different mouse models of androgen deficiency: ORX, androgen receptor (AR) knock-out (ARKO) and sex hormone binding globulin (SHBG)-transgenic mice, a novel mouse model of "low free T". Our results clearly show a fast and dramatic action of T stimulating wheel running, which is not explained by its action on muscle, as evidenced by neuromuscular studies and in a muscle-specific conditional ARKO mouse model. The action of T occurs via its free fraction, as shown by the results in SHBG-transgenic mice, and it implies both androgenic and estrogenic pathways. Both gene expression and functional studies indicate that T modulates the in vivo sensitivity to dopamine (DA) agonists. Furthermore, the restoration of wheel running by T is inhibited by treatment with DA antagonists. These findings reveal that the free fraction of T, both via AR and indirectly through aromatization into estrogens, stimulates physical activity behavior in male mice by acting on central DA pathways.
Scientific reports. 2018 Jan 17*** epublish ***
Ferran Jardí, Michaël R Laurent, Nari Kim, Rougin Khalil, Dimitri De Bundel, Ann Van Eeckhaut, Lawrence Van Helleputte, Ludo Deboel, Vanessa Dubois, Dieter Schollaert, Brigitte Decallonne, Geert Carmeliet, Ludo Van den Bosch, Rudi D'Hooge, Frank Claessens, Dirk Vanderschueren
Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Herestraat 49 PO box 902, 3000, Leuven, Belgium., Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49 PO box 901, 3000, Leuven, Belgium., Department of Pharmaceutical Chemistry and Drug Analysis, VUB, Laarbeeklaan 103, 1090, Brussels, Belgium., Laboratory of Neurobiology, VIB Center for Brain and Disease Research and KU Leuven, Herestraat 49 PO box 602, 3000, Leuven, Belgium., Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, KU Leuven, Tiensestraat 102, 3000, Leuven, Belgium., Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Herestraat 49 PO box 902, 3000, Leuven, Belgium. .