Rajasekaran M Raj, Kanoo Sadhana, Fu Johnny, Nguyen My-Uyen Lilly, Bhargava Valmik, Mittal Ravinder K
Division of Gastroenterology, Department of Medicine, Veterans Affairs San Diego Healthcare System and University of California, San Diego, California;
Department of Urology, Veterans Affairs San Diego Healthcare System and University of California, San Diego, California; and.
Am J Physiol Gastrointest Liver Physiol. 2017 Dec 1;313(6):G581-G588. doi: 10.1152/ajpgi.00209.2017. Epub 2017 Aug 24.
Studies show an age-related increase in the prevalence of anal incontinence and sphincter muscle atrophy. The Wnt/β-catenin signaling pathway has been recently recognized as the major molecular pathway involved in age-related skeletal muscle atrophy and fibrosis. The goals of our study were to ) evaluate the impact of normal aging on external anal sphincter (EAS) muscle length-tension (L-T) function and morphology and ) specifically examine the role of Wnt signaling pathways in anal sphincter muscle fibrosis. New Zealand White female rabbits [6 young (6 mo of age) and 6 old (36 mo of age)] were anesthetized, and anal canal pressure was measured to determine the L-T function of EAS. Animals were killed at the end of the study, and the anal canal was harvested and processed for histochemical studies (Masson trichrome stain for muscle/connective tissue) as well as for molecular markers for fibrosis and atrophy [collagen I, β-catenin, transforming growth factor-β (TGF-β), atrogin-1, and muscle-specific RING finger protein-1 (MuRF-1)]. The L-T was significantly impaired in older animals compared with young animals. Anal canal sections stained with trichrome showed a significant decrease in the muscle content (52% in old compared with 70% in young) and an increase in the connective tissue/collagen content in the old animals. An increased protein and mRNA expression of all the fibrosis markers was seen in the older animals. Aging EAS muscle exhibits impairment of function and increase in connective tissue. Upregulation of atrophy and profibrogenic proteins with aging may be the reason for the age-related decrease in anal sphincter muscle thickness and function. Our studies using a female rabbit model show age-related alterations in the structure and function of the external anal sphincter (EAS) muscle. We used endoluminal ultrasound to measure age-related changes in EAS muscle thickness. We employed Western blot and quantitative PCR to demonstrate age-related changes in the levels of important fibrogenic as well as atrophy markers. Our findings may have significant clinical implications, i.e., use of specific antagonists to prevent age-related EAS muscle dysfunction.
研究表明，肛门失禁和括约肌萎缩的患病率随年龄增长而增加。Wnt/β-连环蛋白信号通路最近被认为是与年龄相关的骨骼肌萎缩和纤维化的主要分子途径。我们研究的目的是：（1）评估正常衰老对外括约肌（EAS）肌肉长度-张力（L-T）功能和形态的影响；（2）具体研究Wnt信号通路在肛门括约肌肌肉纤维化中的作用。将新西兰白兔[6只年轻（6月龄）和6只年老（36月龄）]麻醉，测量肛管压力以确定EAS的L-T功能。在研究结束时处死动物，采集肛管并进行组织化学研究（用于肌肉/结缔组织的Masson三色染色）以及纤维化和萎缩的分子标记物[I型胶原蛋白、β-连环蛋白、转化生长因子-β（TGF-β）、atrogin-1和肌肉特异性环状指蛋白-1（MuRF-1）]检测。与年轻动物相比，老年动物的L-T功能明显受损。三色染色的肛管切片显示老年动物的肌肉含量显著降低（老年为52%，年轻为70%），结缔组织/胶原蛋白含量增加。老年动物中所有纤维化标记物的蛋白质和mRNA表达均增加。衰老的EAS肌肉表现出功能受损和结缔组织增加。随着年龄增长，萎缩和促纤维化蛋白的上调可能是肛门括约肌肌肉厚度和功能随年龄下降的原因。我们使用雌性兔模型的研究显示了外括约肌（EAS）肌肉结构和功能的年龄相关变化。我们使用腔内超声测量EAS肌肉厚度的年龄相关变化。我们采用蛋白质印迹法和定量PCR来证明重要的促纤维化以及萎缩标记物水平的年龄相关变化。我们的发现可能具有重要的临床意义，即使用特定拮抗剂预防与年龄相关的EAS肌肉功能障碍。
