The anabolic effects of androgens on skeletal muscles are thought to be mediated predominantly through the androgen receptor (AR), a member of the ligand-dependent nuclear receptor superfamily. However, despite numerous studies performed in men and in rodents, these effects remain poorly understood. To characterize androgen signaling in skeletal muscles, we generated mice in which the AR is selectively ablated in myofibers. We show that myocytic AR controls androgen-induced insulin-like growth factor IEa (IGF-IEa) expression in the highly androgen-sensitive perineal muscles and that it mediates androgen-stimulated postnatal hypertrophy of these muscles. In contrast, androgen-dependent postnatal hypertrophy of limb muscle fibers is independent of myocytic AR. Thus, androgens control perineal and limb muscle mass in male mice through myocytic AR-dependent and -independent pathways, respectively. Importantly, we also show that AR deficiency in limb myocytes impairs myofibrillar organization of sarcomeres and decreases muscle strength, thus demonstrating that myocytic AR controls key pathways required for maximum force production. These distinct androgen signaling pathways in perineal and limb muscles may allow the design of screens to identify selective androgen modulators of muscle strength.androgens | insulin-like growth factor | perineal muscles | sarcopenia | mouse L oss of muscle mass and function is a feature of various diseases (e.g., neuromuscular disorders, cancer, sepsis, and AIDS), immobilization following acute injuries, and aging that greatly impairs the quality of life for affected patients. Clinical studies indicate that testosterone replacement in young and old hypogonadal men (1-9), as well as in men with sarcopenia associated with chronic illness (10, 11), increases skeletal muscle mass and strength. However, other clinical studies indicate that androgens stimulate muscle mass but not strength (12)(13)(14). Moreover, despite the use of androgenic steroids by athletes, the effects of these agents on athletic performance and physical functions remain poorly characterized (15).In rodents, perineal skeletal muscles [bulbocavernosus (BC) and levator ani (LA), collectively BC/LA] are highly androgen sensitive (16). Indeed, postnatal gonadal testosterone production in males increases BC/LA muscle fiber number and muscle fiber hypertrophy at puberty (17, 18). At adulthood BC/LA fiber size decreases markedly after castration and increases with androgen treatment (19-22), but fiber number remains unchanged (23). In contrast, androgen effects on limb muscle mass and function in animal models remain controversial. Indeed, studies in mice indicate that androgen withdrawal by castration reduces fast-twitch hindlimb muscle mass and maximum force production (24, 25), whereas testosterone administration to orchidectomized male mice prevents hindlimb skeletal muscle atrophy and enhances fatigue resistance of soleus muscle (26). However, it also was reported that administration of the testosterone derivative stanozo...

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-α (ERα)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERα signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERα-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERα-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERα-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERα-positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERα-negative breast cancer, also opportunely combined with antiestrogen therapy. -Mauro, L., Naimo, G. D., Gelsomino, L., Malivindi, R., Bruno, L., Pellegrino, M., Tarallo, R., Memoli, D., Weisz, A., Panno, M. L., Andò, S. Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer.