Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength
- 29 January 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 371 (6528), 483-+
- https://doi.org/10.1126/science.abc8059
Abstract
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.Keywords
Funding Information
- National Institutes of Health (5R01AG02096115)
- National Institutes of Health (1R01AG069858-01)
- National Institutes of Health (RHG009674A)
- National Institutes of Health (K99NS120278)
- National Institutes of Health (1S10OD026962-01)
- National Institutes of Health (1S10RR026780-01)
- California Institute for Regenerative Medicine (DISC2-10604)
- Li Ka Shing Foundation
- Donald E. and Delia B. Baxter Foundation
- Swiss National Science Foundation (P2EZP3_184231)
- Swiss National Science Foundation
- Canadian Institutes of Health Research
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