Abnormal expression of p27kip1 protein in levator ani muscle of aging women with pelvic floor disorders – a relationship to the cellular differentiation and degeneration

Abstract

Background: Pelvic floor disorders affect almost 50% of aging women. An important role in the pelvic floor support belongs to the levator ani muscle. The p27/kip1 (p27) protein, multifunctional cyclin-dependent kinase inhibitor, shows changing expression in differentiating skeletal muscle cells during development, and relatively high levels of p27 RNA were detected in the normal human skeletal muscles.

Combined estrogen and ghrelin administration decreases expression of p27kip1 and proportion of isomyosin type I in the striated urethral and anal sphincters and levator ani of old ovariectomized rats

“…Overexpression of muscular cytoplasmic p27 kip1 is involved in apoptosis via the Fas ligand pathway that could be accelerated by estrogen deprivation similar to other cell types including neurons, endothelial cells, epithelial cells of the female reproductive tract, and hormone-dependent breast cancer [25]. Elderly postmenopausal women with urinary or fecal incontinence thus show strong expression of cytoplasmic p27 kip1 in the levator ani muscle cells associated with cellular shrinking and fragmentation compared to younger postmenopausal or peri-menopausal patients, as seen in our animal model [7]. Likewise, skeletal muscle gene expression profiles of p27 kip1 are increased in elderly women reflecting increased DNA damage and increased fiber regeneration [23].…”

“…We did not, however, compare the effect of estrogen and/ or ghrelin on post-ovariectomy cytoplasmic expression of p27 kip1 in striated pelvic floor muscles (striated urethral and anal sphincters and levator ani) in old as opposed to young adult rats [7,8]. p27 kip1 is a cyclin-dependent kinase inhibitor required for cell cycle arrest that normally regulates muscle differentiation and apoptosis and increased cytoplasmic expression of this protein is one of the specific biomarkers of striated muscle cell ageing in humans [7,8].…”

“…p27 kip1 is a cyclin-dependent kinase inhibitor required for cell cycle arrest that normally regulates muscle differentiation and apoptosis and increased cytoplasmic expression of this protein is one of the specific biomarkers of striated muscle cell ageing in humans [7,8]. We did not also investigate whether these hormones can influence a third continence mechanism, the relative proportion of isomyosin fibers type I and II in the striated pelvic floor muscles [8][9][10][11][12][13].…”

Genetics and the lower urinary tract

“…7 Collagen and the enzymes which modify them (collagenases or metalloproteinases) have been implicated in the development of lower urinary tract disorders. Matrix metalloproteinases (MMPs) have been observed to be increased in patients with pelvic floor disorders including prolapse and incontinence 8 (Zong, 2005) Other recent candidate gene studies have focused on genes related to skeletal muscle myosin, 9 p27/kip1, 10 and the basement membrane protein laminin LAMC1. 11 Several groups are currently exploring these possibilities looking for SNPs in larger groups of patients with UI.…”

Basic science and translational research in female pelvic floor disorders: Proceedings of an NIH‐sponsored meeting

“…Premenopausal women will virtually always be younger than postmenopausal women and they may have lower parity as well [Heit et al, 1996]. The appropriate interpretation of ¢ndings requires asymptomatic controls that are similar in age, menopausal status, and parity for comparison [Bukovsky et al, 2001].…”