![]() Locomotion is a well-established sexually dimorphic behavior in rodents 5 that responds to androgens and estrogens 6, 7. Over the past several years, new insights have revealed the existence of a neurophysiological basis regulating the motivation to engage in regular physical exercise. It is of no surprise, therefore, that implementing regular exercise on a population level has become a key priority in public health policy. The lack of regular exercise is estimated to cause 6% of the burden of disease from coronary heart disease, 7% of type 2 diabetes and 10% of both breast and colon cancer 3, and accounts for 1.5–3.0% of direct healthcare costs 4. Less than 50% of the adult Western population meets the minimum levels of recommended moderate-to-vigorous exercise, whilst spending 60% of their time in sedentary pursuits 1, 2. Physical inactivity has emerged as a global epidemic. 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. Furthermore, the restoration of wheel running by T is inhibited by treatment with DA antagonists. Both gene expression and functional studies indicate that T modulates the in vivo sensitivity to dopamine (DA) agonists. 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. 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. 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”. Still, the mechanisms through which T stimulates activity remain mostly obscure. ![]() In accordance, orchidectomy (ORX) in rodents results in decreased physical activity. Low testosterone (T) in men, especially its free fraction, has been associated with loss of energy.
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