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


ABSTRACT: Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. We identifed increased amounts of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE2 signaling contributed to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells, such as macrophages, within muscle. Overexpression of 15-PGDH in young muscles induced atrophy. Inhibition of 15-PGDH, by targeted genetic depletion or a small-molecule inhibitor, increased aged muscle mass, strength, and exercise performance. These benefits arise from a physiological increase in PGE2 concentrations, which augmented mitochondrial function and autophagy and decreased transforming growth factor-? signaling and activity of ubiquitin-proteasome pathways. Thus, PGE2 signaling ameliorates muscle atrophy and rejuvenates muscle function, and 15-PGDH may be a suitable therapeutic target for countering sarcopenia.

SUBMITTER: Palla AR 

PROVIDER: S-EPMC7938328 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Palla A R AR   Ravichandran M M   Wang Y X YX   Alexandrova L L   Yang A V AV   Kraft P P   Holbrook C A CA   Schürch C M CM   Ho A T V ATV   Blau H M HM  

Science (New York, N.Y.) 20201210 6528


Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. We identifed increased amounts of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the prostaglandin E<sub>2</sub> (PGE<sub>2</sub>)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE<sub>2</sub> signaling contributed to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells, such as macrophages, wit  ...[more]

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