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Science ; 371(6528)2021 01 29.
Article in English | MEDLINE | ID: mdl-33303683

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-ß 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.


Subject(s)
Aging/metabolism , Dinoprostone/metabolism , Hydroxyprostaglandin Dehydrogenases/physiology , Muscle, Skeletal/pathology , Rejuvenation , Sarcopenia/enzymology , Animals , Autophagic Cell Death/genetics , Autophagic Cell Death/physiology , Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors , Hydroxyprostaglandin Dehydrogenases/genetics , Macrophages/enzymology , Mice , Mice, Inbred C57BL , Mitochondria, Muscle/ultrastructure , Muscle Strength/genetics , Muscle Strength/physiology , Muscle, Skeletal/enzymology , Myofibrils/enzymology , Sarcopenia/genetics
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