Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary.
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Date
2022
Authors
Umehara, T.
Winstanley, Y.E.
Andreas, E.
Morimoto, A.
Williams, E.J.
Smith, K.M.
Carroll, J.
Febbraio, M.A.
Shimada, M.
Russell, D.L.
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Journal article
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Science Advances, 2022; 8(24):eabn4564-1-eabn4564-17
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Takashi Umehara, Yasmyn E. Winstanley, Eryk Andreas, Atsushi Morimoto, Elisha J. Williams, Kirsten M. Smith, John Carroll, Mark A. Febbraio, Masayuki Shimada, Darryl L. Russell, Rebecca L. Robker
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Abstract
The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and dis-ordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflam-mation, and collagen deposition. Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macro-phage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.
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Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC)