期刊
SCIENCE
卷 371, 期 6528, 页码 483-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc8059
关键词
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资金
- Baxter Foundation
- California Institute for Regenerative Medicine [DISC2-10604]
- U.S. National Institutes of Health (NIH) [5R01AG02096115, 1R01AG069858-01, RHG009674A]
- National Institutes of Health Shared Instrumentation grant [S10OD026962]
- Canadian Institutes of Health Research
- SNF Early Postdoc Mobility Fellowship [P2EZP3_184231]
- SNF Postdoc Mobility Fellowship
- National Center for Research Resources (NCRR) [1S10RR026780-01]
- Li Ka Shing Foundation
- NIH K99 award [K99NS120278]
- Swiss National Science Foundation (SNF) [P2EZP3_184231] Funding Source: Swiss National Science Foundation (SNF)
The study found that muscle atrophy in aged mice is mainly due to the increase of 15-PGDH leading to the decrease in PGE(2) signaling, while inhibition of 15-PGDH can increase the quality, strength, and exercise performance of aged muscle.
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-2 (PGE(2))-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE(2) signaling contributed to musde 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 PGE(2) concentrations, which augmented mitochondrial function and autophagy and decreased transforming growth factor-beta signaling and activity of ubiquitinproteasome pathways. Thus, PGE(2) signaling ameliorates muscle atrophy and rejuvenates muscle function, and 15-PGDH may be a suitable therapeutic target for countering sarcopenia.
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