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Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength

Authors: A R Palla , M Ravichandran, Y X Wang, L Alexandrova, A V Yang, P Kraft , C A Holbrook, C M Schürch, A T V Ho, H M Blau

Online: https://science.sciencemag.org/content/early/2020/12/09/science.abc8059

Issue: Science. 2020 Dec 10;eabc8059.


Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. Here we identify elevated 15-PGDH, the Prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The resulting reduction in PGE2 signaling is a major contributor to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells within muscle. Inhibition of 15-PGDH, by targeted genetic knockdown or a small molecule inhibitor, increases aged muscle mass, strength, and exercise performance. These physiological benefits arise from rejuvenated PGE2 levels which augment mitochondrial function and autophagy and decrease TGF-beta and ubiquitin-proteasome pathways. Our studies demonstrate a previously unrecognized role for PGE2 signaling in countering muscle atrophy and identify 15-PGDH as a promising therapeutic target to counter sarcopenia.