Lack of retinoid acid receptor-related orphan receptor alpha accelerates and melatonin supplementation prevents testicular aging

Abstract

The role of retinoid acid receptor-related orphan receptor alpha (RORα) on male reproductive functions during aging is unclear. Here, we analyze the morphological changes in the testis of both young and aged RORα-deficient mice, with and without melatonin supplementation. Young mutants showed vacuolation, degeneration and pyknosis of spermatogenic epithelium and Sertoli cells. Aged mutants showed atrophy of the seminiferous tubules and absence of mitotic spermatogenic cells. Absence of sperms in many tubules, loss of acrosomal cap, vacuolation and hypertrophy of Sertoli cells were detected in aged mice, with a significant reduction in the number of seminiferous tubules and a significant increase in the number of Leydig cells and telocytes. Repair in seminiferous tubules and interstitial tissues with enhancement of spermatogenesis was observed in melatonin-treated aged mice. Young mutants overexpressed VEGF that was weaker in aged animals and observed only in the spermatocytes, while melatonin increased VEGF expression in spermatocytes and spermatids. Caspase 3 increased in both young and aged mutant mice in all seminiferous tubules and interstitium; caspase 3 immunostaining in seminiferous tubules, however, showed a normal pattern of apoptosis with melatonin supplementation. The present study reports that age-dependent testicular changes in RORα mutant mice were recovered by melatonin treatment.

Telocytes of the male urogenital system: Interrelationships, possible functions, and pathological implications

“…In these animals, other structural changes in the gland are seen, such as problems in the maturation of sperm and hypertrophy of Sertoli cells. In addition, Leydig cells also increase their presence in the testes with senescence (Sayed et al, 2020), taken together these data indicate that the telocytes in the testis may be sensitive to other molecular pathways in addition to the estrogenic and androgenic ones. With regard to other possible functions of the telocytes in the testes, these cells may participate in the transport of multilamellar bodies.…”

Inverse Agonist of Retinoid-Related Orphan Receptor-Alpha Prevents Apoptosis and Degeneration in Nucleus Pulposus Cells via Upregulation of YAP

“…ROR α plays a complex role in regulating apoptosis in different cell types. Loss of ROR α results in progressive, diverse testicular damage and leads to apoptosis, suggesting that ROR α knockout promotes apoptosis in the testicle [ 35 ]. However, other studies revealed the proapoptosis effect of ROR α in different cell types [ 36 , 37 ], suggesting the complexity of ROR α in regulating cell senescence and apoptosis.…”

Testicular aging, male fertility and beyond

“…In addition, exogenous adiponectin treatment has been reported to significantly improve the testicular size, cell proliferation, insulin receptor expression, glucose uptake, antioxidant enzyme activity, and testosterone synthesis in aged mice ( 148 ). Melatonin supplementation could also rescue testicular aging caused by the loss of retinoic acid receptor-related orphan receptor alpha ( 53 ).…”