Loss of resilience contributes to detrusor underactivity in advanced age.
Loss of resilience contributes to detrusor underactivity in advanced age.
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DOI：
10.1007/s10522-022-10005-y
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发表时间：
2023-04
期刊：
影响因子：
4.5
通讯作者：
Smith, Phillip P. P.
中科院分区：
文献类型：
--
作者：
Ramasamy, Ramalakshmi;Baker, Dylan S. S.;Lemtiri-Chlieh, Fouad;Rosenberg, Dawn A. A.;Woon, Eric;Al-Naggar, Iman M. M.;Hardy, Cara C. C.;Levine, Eric S. S.;Kuchel, George A. A.;Bartley, Jenna M. M.;Smith, Phillip P. P.
膀胱充盈过程中交感神经逼尿肌松弛受损导致容量敏感性降低，导致与衰老相关的逼尿肌活动不足（DU）。逼尿肌张力调节为脑干提供了膀胱容量的适应性感觉输入，并受到生物衰老叠加的生理压力源的挑战。我们最近表明 HCN 通道在逼尿肌交感神经松弛中具有稳定作用。虽然成熟的小鼠在面对压力时能够保持体内平衡，但年老的小鼠并不总是有能力。在老年小鼠中，存在二分表型，其中有弹性的小鼠能够适应并维持体内平衡，而无弹性的小鼠则无法维持生理稳态。在此 DU 模型中，我们使用膀胱测压作为压力源，将小鼠分类为老反应者（old-R，产生充盈/排尿循环）或老无反应者（old-NR，未能形成充盈/排尿循环；高压波动和持续渗漏），同时还评估功能和分子差异。在 HCN 阻断后，老年 NR 小鼠中拉莫三嗪（HCN 激活剂）诱导的膀胱松弛减弱。老年 NR 小鼠对 NS 1619 的松弛反应减弱，HCN 阻断后效果消失。然而，RNA测序显示HCN基因表达没有差异，电生理学研究显示old-R和old-NR小鼠之间当前表达HCN (Ih)的逼尿肌细胞百分比相似。我们的 DU 小鼠模型进一步定义了 HCN 的作用，HCN 参与和 HCN 介导的稳定强度的适应性重新校准失败，而基因组研究显示老年 NR 小鼠中肌成纤维细胞和纤维化途径上调，神经递质降解途径下调。因此，DU 表型是多因素的，代表了体内平衡机制中与年龄相关的损失的积累。
Volume hyposensitivity resulting from impaired sympathetic detrusor relaxation during bladder 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 assessing functional and molecular differences. Lamotrigine (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 electrophysiology 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 recalibration of HCN participation and intensity of HCN-mediated stabilization, while genomic studies show upregulated myofibroblast and fibrosis pathways and downregulated neurotransmitter-degradation pathways in old-NR mice. Thus, the DU phenotype is multifactorial and represents the accumulation of age-associated loss in homeostatic mechanisms.
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DOI：
10.1093/gerona/gly137
发表时间：
2019-03-01
影响因子：
5.1
作者：
Al-Naggar, Iman M.;Hardy, Cara C.;Smith, Phillip P.
通讯作者：
Smith, Phillip P.
影响因子：
2
作者：
Abrams, Paul;Artibani, Walter;Sand, Peter
通讯作者：
Sand, Peter
影响因子：
23.4
作者：
Chapple, Christopher R.;Osman, Nadir I.;Smith, Philip P.
通讯作者：
Smith, Philip P.
影响因子：
64.5
作者：
Kolfschoten, IGM;van Leeuwen, B;Agami, R
通讯作者：
Agami, R
影响因子：
6.6
作者：
Gomez-Pinilla, Pedro J.;Gomez, Maria F.;Andersson, Karl-Erik
通讯作者：
Andersson, Karl-Erik