Ikedo, A. | Search bioRxiv

bioRxiv2024

Aromatase in adipose tissue exerts an osteoprotective function in male mice via phosphate regulation

Aromatase contributes to maintenance of bone mass because male patients with loss-of-function mutations of CYP19A1 exhibit bone loss. Treatment with aromatase inhibitor also causes bone loss in men and post-menopausal women, suggesting that part of the anabolic effect of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. It remains unclear how locally biosynthesized E2 contributes to maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonads using cell-type specific aromatase knockout (KO) mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, known as a reservoir of steroid hormones and analyzed the bone phenotypes of adipose tissue-specific aromatase KO (Aro{Delta}aP2) mice. Sixteen-week-old male Aro{Delta}aP2 mice exhibited significantly lower bone mineral density in tibia and femur, especially in trabecular bone, than controls. Bone histomorphometry showed that Aro{Delta}aP2 mice exhibited an insufficient calcification bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum phosphate, renal phosphate reabsorption and FGF23 were significantly lower in Aro{Delta}aP2, suggesting that the insufficient calcification phenotype in Aro{Delta}aP2 was not caused by excessive FGF23 activities. Finally, we analyzed NaPi2a and NaPi2c, phosphate transporters localized in the kidney, and found that protein levels in renal brush border membrane vesicles were lower in Aro{Delta}aP2. These results indicate that estrogens locally biosynthesized by aromatase in adipocytes can play a significant role in bone mass maintenance via regulation of phosphate reabsorption in the kidney by NaPi2. Impact StatementMale adipocyte-specific aromatase KO mice (Aro{Delta}aP2) exhibited bone loss and increased osteoid due to decreased serum phosphate and urinary phosphate reabsorption as a result of reduced NaPi2 proteins expression in the kidney.

physiology↗

bioRxiv2023

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via extra-myofiber cells or tissues. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1), and that IGF1 administration prevents perineal muscles atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors. Significance statementAndrogens are essential not only for the development of male sexual characteristics but also for a range of physiological functions, including the regulation of skeletal muscle growth and function. Understanding the functionality of the androgen receptor (AR) is essential for comprehending the mechanisms through which androgens exert their effects on skeletal muscles, as these effects are mediated through AR binding. We demonstrate that AR is expressed in mesenchymal progenitors, which play a vital role in muscle homeostasis, and regulates the expression of insulin-like growth factor 1 (Igf1)--a key player in skeletal muscle growth--to control muscle mass. Our study provides significant insights into potential therapeutic strategies for addressing muscle atrophy conditions like sarcopenia.

molecular biology↗