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Ageing-related bladder dysfunctions and their gender differences in mice: in vitro and in vivo functional and gene expression changes

ABSTRACT: Objective To investigate aging-related changes and their sex differences in in vivo and in vitro functions and gene expression in the bladder of mice. Materials and Methods Mature (12-month old) and aged (27–30-month old) mice of both sexes were studied. In in vivo experiments, frequency, volume, and conscious free-moving cystometry measurements were investigated. In in vitro experiments, organ bath studies using detrusor strips were performed to observe functional changes, and serum sex hormone levels and mRNA expression of muscarinic, purinergic, and β-adrenergic receptors in the bladder using a cDNA microarray were evaluated. Results Although few differences were detected in the frequency/volume measurements between the two groups in either sex, aged mice showed a lower mean flow rate and higher number of non-voiding contractions in both sexes and lower maximum pressure and smaller voided volume and bladder capacity was observed in males according to cystometry measurements. Detrusor strips from aged mice showed weaker contractile responses to carbachol and electrical field stimulation, particularly in the cholinergic component, and relaxant responses to isoproterenol, which were accompanied by a decreased mRNA expression of M3 muscarinic receptors in aged males and β2-adrenoceptors in aged females. This aging-related bladder dysfunction was more severe in males, and the serum testosterone level in aged males was significantly decreased. Gene expression changes in the bladder with aging were different between sexes: 469 and 544 genes in males, 392 and 75 in females, and 8 and 37 in both sexes were significantly upregulated and downregulated, respectively, with aging. Conclusions Aged mice of both sexes demonstrated both voiding and storage dysfunctions, which were more pronounced in males. Sex hormone and genomic changes associated with aging may contribute to this functional deterioration in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE100219 | GEO | 2018/02/13

REPOSITORIES: GEO

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Project description:Microglia, the brain’s principal immune cells, have been implicated in the pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic findings. There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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Ageing-related bladder dysfunctions and their gender differences in mice: in vitro and in vivo functional and gene expression changes

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