Impact of Androgens, Growth Hormone, and IGF-I on Bone and Muscle in Male Mice During Puberty

Abstract

ABSTRACT:The interaction between androgens and GH/IGF-I was studied in male GHR gene disrupted or GHRKO and WT mice during puberty. Androgens stimulate trabecular and cortical bone modeling and increase muscle mass even in the absence of a functional GHR. GHR activation seems to be the main determinant of radial bone expansion, although GH and androgens are both necessary for optimal stimulation of periosteal growth during puberty.Introduction: Growth hormone (GH) is considered to be a major regulator of postnatal skeletal growth, whereas androgens are considered to be a key regulator of male periosteal bone expansion. Moreover, both androgens and GH are essential for the increase in muscle mass during male puberty. Deficiency or resistance to either GH or androgens impairs bone modeling and decreases muscle mass. The aim of the study was to investigate androgen action on bone and muscle during puberty in the presence and absence of a functional GH/insulin-like growth factor (IGF)-I axis. Materials and Methods: Dihydrotestosterone (DHT) or testosterone (T) were administered to orchidectomized (ORX) male GH receptor gene knockout (GHRKO) and corresponding wildtype (WT) mice during late puberty (6-10 weeks of age). Trabecular and cortical bone modeling, cortical strength, body composition, IGF-I in serum, and its expression in liver, muscle, and bone were studied by histomorphometry, pQCT, DXA, radioimmunoassay and RT-PCR, respectively. Results: GH receptor (GHR) inactivation and low serum IGF-I did not affect trabecular bone modeling, because trabecular BMD, bone volume, number, width, and bone turnover were similar in GHRKO and WT mice. The normal trabecular phenotype in GHRKO mice was paralleled by a normal expression of skeletal IGF-I mRNA. ORX decreased trabecular bone volume significantly and to a similar extent in GHRKO and WT mice, whereas DHT and T administration fully prevented trabecular bone loss. Moreover, DHT and T stimulated periosteal bone formation, not only in WT (+100% and +100%, respectively, versus ORX + vehicle [V]; p < 0.05), but also in GHRKO mice (+58% and +89%, respectively, versus ORX + V; p < 0.05), initially characterized by very low periosteal growth. This stimulatory action on periosteal bone resulted in an increase in cortical thickness and occurred without any treatment effect on serum IGF-I or skeletal IGF-I expression. GHRKO mice also had reduced lean body mass and quadriceps muscle weight, along with significantly decreased IGF-I mRNA expression in quadriceps muscle. DHT and T equally stimulated muscle mass in GHRKO and WT mice, without any effect on muscle IGF-I expression. Conclusions: Androgens stimulate trabecular and cortical bone modeling and increase muscle weight independently from either systemic or local IGF-I production. GHR activation seems to be the main determinant of radial bone expansion, although GHR signaling and androgens are both necessary for optimal stimulation of periosteal growth during puberty.

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

“…(44) Nonetheless, despite this limitation, these data support our hypothesis that the important action of androgens to increase periosteal apposition during growth is mediated autonomously via the AR in proliferating osteoblasts located at the periosteum. (19,45) In line with this hypothesis, no effect of replacing the AR at the mineralization stage of osteoblast maturation was observed on periosteal circumference in mOBL-AR gene replacement mice.…”

Food Restriction Causes Low Bone Strength and Microarchitectural Deterioration in Exercised Growing Male Rats

“…For example, androgen directly binds to androgen receptor on osteoclasts and blocks bone resorption in human, mouse, and avian osteoclasts in vitro (30). Actually, a previous study reported that low androgen levels led to decreased BMD in growing male mice (14). In contrast, long-term food restriction revealed that the testosterone level did not change, although short-term food restriction decreased the testosterone level in male rats (31).…”

“…Low energy availability involves the endocrine system and decreases androgen levels (15). Low androgen levels are known to affect bone metabolism and cause bone fragility (14). Actually, severe food restriction tends to remarkably lower bone mineral content in distal femurs, which mostly consist of trabecular bone in rats (28).…”

“…The energy deficit is disrupted to attenuate the pulsatile luteinizing hormone (LH) through low gonadotropin-releasing hormone (GnRH) secretion (13 6 and Naomi Omi 1,4, decreases androgen secretion by the testis (12). Androgen deficiency leads to high bone turnover, whereby cortical and trabecular bone loss occurs in growing male mice (14). Food restriction may have a harmful effect on bone growth under exercise training.…”

The hormonal action of IGF1 in postnatal mouse growth

“…This realization excludes as contributors all tissues in which Igf1 expression is GH-independent, such as the skeletal system (a sizable component of mouse body weight; approximately 8%) and also the brain, lung, heart, spleen, testis, and uterus (2,19,20). Igf1 gene transcription is GH-dependent in skeletal muscles, adipose tissue, ovary, and kidney (2,(20)(21)(22), although partially, in contrast to the complete dependence of the liver. Of these tissues, however, only the musculature (approximately 35% of body weight) remains a candidate for an auxiliary source of serum IGF1 (see below).…”