Lack of sexual dimorphism in femora of the eusocial and hypogonadic naked mole-rat: A novel animal model for the study of delayed puberty on the skeletal system

Abstract

Sex steroid hormones are major determinants of bone morphology and quality and are responsible for sexually dimorphic skeletal traits. Hypogonadism results in suboptimal skeletal development and may lead to an increased risk of bone fracture later in life. The etiology of delayed puberty and/or hypothalamic amenorrhea is poorly understood, and experimental animal models addressing this issue are predominantly based upon short-term experimental induction of hormonal suppression via gonadotropin releasing hormone antagonists (GnRH-a). This acute change in hormone profile does not necessarily emulate the natural progression of hypogonadic bone disorders. We propose a novel animal model with which to explore the effects of chronic hypogonadism on bone quality, the naked mole-rat (NMR; Heterocephalus glaber). This mouse-size rodent may remain reproductively suppressed throughout its life, if it remains as a subordinate within the eusocial mole-rat colony. NMRs live in large colonies with a single dominant breeding female. She, primarily by using aggressive social contact, naturally suppresses the hypothalamic gonadotropic axis of subordinate NMRs and thereby their reproductive expression. However should an NMR be separated from the dominant breeder, within less than a week reproductive hormones may become elevated and the animal attains breeding status. We questioned if sexual suppression of subordinates impact upon the development and maintenance of the femora, and lead to a sexually indistinct monomorphic skeleton. Femora were obtained from male and female NMRs that were either non-breeders (subordinate) or breeders at the time of sacrifice. Diaphyseal cross-sectional morphology, metaphyseal trabecular micro-architecture and tissue mineral density of the femur was measured using MicroComputed tomography and diaphyseal mechanical properties were assessed by four-point bending tests to failure. Subordinates were sexually monomorphic and showed no significant differences in body weight or femoral bone structure and quality between male and females. Femora of subordinate females differed significantly from that of breeding animals, whereas in males, the divergent trend among breeders and non-breeders did not reach statistical significance. Subordinate NMRs, naturally suppressed from entering puberty, may prove to be a useful model to tease apart the relationship between bone morphology and hypogonadism and evaluate skeletal development during pubertal maturation.

Extended Postnatal Brain Development in the Longest-Lived Rodent: Prolonged Maintenance of Neotenous Traits in the Naked Mole-Rat Brain

“…We questioned whether previous reports of neotenous traits in NMRs indicate a failure to mature, associated with delayed reproduction in subordinates (Jarvis, 1981; Pinto et al, 2010), or simply a difference in developmental heterochrony when compared to similar-sized rodents. Unlike commonly studied laboratory mice and rats, which complete brain maturation by 3 and 6 weeks of age, respectively, we found that NMR brain development tracks more closely with long-lived species (e.g., humans and non-human primates).…”

“…This has been attributed to their retained expression of a neonatal NMDA receptor subunit that is less sensitive to hypoxic conditions (Peterson et al, 2012a,b). Other neotenous traits include unfused growth plates in bone (Pinto et al, 2010), immature lung morphology (Maina et al, 1992). Moreover, many of the described NMR brain features are suggestive of an extended period of development or persistent neoteny as well.…”

Postnatal development of the largest subterranean mammal (Bathyergus suillus): Morphology, osteogenesis, and modularity of the appendicular skeleton

“…Despite femora reaching higher bone compactness than the humerus, a systemic genetic regulation for bone thickening is more plausible rather than mechanical stimulation of a single limb (forelimb). In addition, non‐reproductive colony members born in captivity of the eusocial Heterocephalus glaber , still develop thick cortical bone walls before reaching sexual maturity . This information suggests that genetic factors are more likely to influence the development of cortical bone thickening in Bathyergus and other bathyergids.…”

Spontaneous Histologic Lesions of the Adult Naked Mole Rat (Heterocephalus glaber)

“…16 Examples of these virtually unchanged parameters include basal metabolic rate; vascular health and relaxation; bone and cartilage integrity and mineral density; ROS production, antioxidant activity, and oxidative damage; glucose tolerance; and glycated hemoglobin. 3,19,22,32,60,74,82,100 Current studies are examining the stability of the genome and proteins with age. 58,101 For example, sustained high levels of neuregulin-1 were documented in aged NMRs, suggesting that one mechanism of longevity is stability of neuregulin signaling and sustained brain function.…”