Blau Laboratory, Stanford School of Medicine, Stanford, CA 94305, USA.
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
Science. 2021 Jan 29;371(6528). doi: 10.1126/science.abc8059. Epub 2020 Dec 10.
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 (PGE)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE 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 PGE concentrations, which augmented mitochondrial function and autophagy and decreased transforming growth factor-β signaling and activity of ubiquitin-proteasome pathways. Thus, PGE signaling ameliorates muscle atrophy and rejuvenates muscle function, and 15-PGDH may be a suitable therapeutic target for countering sarcopenia.
对于肌肉减少症（一种与年龄相关的骨骼肌肉消耗综合征），目前缺乏有效的治疗方法。我们发现，15-羟基前列腺素脱氢酶（15-PGDH）——一种降解前列腺素 E（PGE）的酶——在包括骨骼肌在内的老年组织中大量增加，是其特征之一。由此导致的 PGE 信号转导减少导致老年小鼠的肌肉萎缩，并且源于表达 15-PGDH 的肌纤维和肌肉内的间质细胞（如巨噬细胞）。在年轻肌肉中过表达 15-PGDH 会诱导肌肉萎缩。通过靶向基因缺失或小分子抑制剂抑制 15-PGDH，可增加老年肌肉的质量、力量和运动表现。这些益处源于 PGE 浓度的生理性增加，这增加了线粒体功能和自噬，减少了转化生长因子-β信号和泛素-蛋白酶体途径的活性。因此，PGE 信号转导可改善肌肉萎缩并恢复肌肉功能，15-PGDH 可能是对抗肌肉减少症的合适治疗靶点。
