Loss of resilience contributes to detrusor underactivity in advanced age.
Loss of resilience contributes to detrusor underactivity in advanced age. Biogerontology. 2023;24(2):163-81.
JGM, Mice, Animals, Urinary Bladder, Underactive, Urinary Bladder, Aging
National Institutes of Health R01AG058814; K02AG068375; K76AG054777. JB and GAK were supported by the UConn Claude D. Pepper Older Americans Independ- ence Center (P30AG067988).
Volume hyposensitivity resulting from impaired sympathetic detrusor relaxation during blad- der filling contributes to detrusor underactivity (DU) associated with aging. Detrusor tension regulation provides an adaptive sensory input of bladder volume to the brainstem and is challenged by physiological stressors superimposed upon biological aging. We recently showed that HCN channels have a stabilizing role in detrusor sympathetic relaxation. While mature mice maintain homeostasis in the face of stressors, old mice are not always capable. In old mice, there is a dichotomous phenotype, in which resilient mice adapt and maintain homeostasis, while non-resilient mice fail to maintain physiologic homeostasis. In this DU model, we used cystometry as a stressor to categorize mice as old-responders (old-R, develop a filling/voiding cycle) or old-non-responders (old-NR, fail to develop a filling/voiding cycle; fluctuating high pressures and continuous leaking), while also assess- ing functional and molecular differences. Lamotrig- ine (HCN activator)-induced bladder relaxation is diminished in old-NR mice following HCN-blockade. Relaxation responses to NS 1619 were reduced in old-NR mice, with the effect lost following HCN- blockade. However, RNA-sequencing revealed no differences in HCN gene expression and electrophysi- ology studies showed similar percentage of detrusor myocytes expressing HCN (Ih) current between old-R and old-NR mice. Our murine model of DU further defines a role for HCN, with failure of adaptive recal- ibration of HCN participation and intensity of HCN- mediated stabilization, while genomic studies show upregulated myofibroblast and fibrosis pathways and downregulated neurotransmitter-degradation path- ways in old-NR mice. Thus, the DU phenotype is multifactorial and represents the accumulation of age- associated loss in homeostatic mechanisms.