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

doi:10.1126/science.abc8059

GSTDTAP > 气候变化

DOI	10.1126/science.abc8059
	Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength
	A. R. Palla; M. Ravichandran; Y. X. Wang; L. Alexandrova; A. V. Yang; P. Kraft; C. A. Holbrook; C. M. Schürch; A. T. V. Ho; H. M. Blau
	2021-01-29
发表期刊	Science
出版年	2021
英文摘要	Prostaglandin E2 (PGE2), an eicosanoid that mediates inflammatory responses, also supports the function of muscle stem cells. Palla et al. found that loss of PGE2 in aging mice contributes to loss of muscle and appears to be a consequence of increased activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that degrades PGE2 (see the Perspective by Becker and Rudolph). Restoring PGE2 concentrations by inhibiting 15-PGDH in older mice improved muscle function. Decreased activity of 15-PGDH in older animals had beneficial effects that included decreased proteolysis and transforming growth factor–β signaling and increased mitochondrial function and autophagy. The findings reveal a potential therapeutic strategy to help maintain muscle mass and function during aging. Science , this issue p. [eabc8059][1]; see also p. [462][2] ### INTRODUCTION Currently there are no approved treatments for sarcopenia, the age-dependent loss of skeletal muscle mass and strength that constitutes a major public health problem affecting ~15% of individuals aged 65 or older. This dysfunction is due to aberrant protein and organelle turnover, inflammation, neuromuscular degeneration, and reduced mitochondrial function. Owing to its multifactorial etiology, untangling the causal molecular pathways to identify therapeutic targets to delay or reverse sarcopenia has proven challenging. Here we identify increased accumulation of the prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a hallmark of aged tissues, including skeletal muscle, and show that it can be therapeutically targeted to enhance muscle mass and strength. ### RATIONALE Previously we determined that in young mice, prostaglandin E2 (PGE2), a lipid metabolite generated from membrane fatty acids, stimulates muscle stem cells and is required to repair damaged muscles, in agreement with reports of PGE2’s function in hematopoietic, bone, colon, and liver regeneration. However, there is a paucity of knowledge regarding the role of PGE2 in muscle aging. We hypothesized that PGE2 concentration and signaling go awry in aged tissues. In accordance, we found that PGE2 is reduced as a result of increased amounts of 15-PGDH and that short-term inhibition of this catabolic enzyme suffices to rejuvenate mitochondrial function, induce hypertrophy, and increase aged muscle strength. ### RESULTS Using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to distinguish closely related prostaglandin family members, we determined that concentrations of PGE2 are reduced in aged murine skeletal muscles. We found that the decrease in PGE2 is due to increased prostaglandin catabolism by elevated 15-PGDH. By using multiplex tissue imaging (CODEX, co-detection by indexing) to visualize localization of multiple markers together with 15-PGDH, we identified myofibers and tissue-resident macrophages as the source of 15-PGDH in the aged muscle microenvironment. Inhibition of 15-PGDH, either by localized genetic knockdown using a short hairpin RNA or systemic delivery of a small-molecule inhibitor, countered muscle atrophy and markedly increased the cross-sectional area of myofibers, muscle mass, strength, and endurance in aged mice after 1 month of treatment. The potency of 15-PGDH in mediating an aging phenotype is underscored by the atrophy and loss of muscle mass and strength, observed after 1 month of ectopic expression of the enzyme in muscles of young mice. Genetic loss-of-function experiments confirmed that PGE2 and its receptor EP4 mediate these effects. Mechanistically, inhibition of 15-PGDH in aged muscles affects several signaling pathways: decreasing transforming growth factor–β (TGF-β) signaling and the ubiquitin proteosome pathway and increasing mitochondrial biogenesis and function. Transmission electron microscopy (TEM) of muscles after 15-PGDH inhibition revealed an increase in the number of intermyofibrillar mitochondria and restoration of mitochondria morphology similar to that of young muscles. In accordance with the increase in mitochondrial function, we observed an increase in autophagy flux. These synergistic interactions culminate in a marked increase in muscle mass and strength in sarcopenic aged mice. ### CONCLUSION We identified the prostaglandin-degrading enzyme, 15-PGDH, as a driver of muscle atrophy. Overexpression of this enzyme in young mice induced muscle loss, and short-term inhibition overcame the muscle wasting associated with aging. A major advantage of our approach is that it restores PGE2 in aged muscles to physiological levels characteristic of young muscles. The augmented PGE2 orchestrates several complementary signaling pathways, leading to increased mitochondrial numbers and function. Our findings have broad relevance, as elevated 15-PGDH expression is detected in a multiplicity of aged tissues. The pleiotropic beneficial effects leading to the muscle rejuvenation seen upon inhibition of 15-PGDH identify the enzyme as a pivotal molecular determinant of aging that can be therapeutically targeted to surmount the muscle weakness associated with sarcopenia. ![Figure][3] 15-PGDH inhibition in aged mice leads to increased skeletal muscle mass and strength. The prostaglandin-degrading enzyme, 15-PGDH, is increased in aged muscles and drives age-related muscle atrophy. Inhibition of 15-PGDH by a small molecule or genetic depletion (knockdown) in aged mice leads to increased PGE2, decreased atrogene expression and TGF-β signaling, and increased autophagy and mitochondrial biogenesis and function, culminating in muscle hypertrophy and increased force. 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–β 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. [1]: /lookup/doi/10.1126/science.abc8059 [2]: /lookup/doi/10.1126/science.abf9566 [3]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/314010
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	A. R. Palla,M. Ravichandran,Y. X. Wang,et al. Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength[J]. Science,2021.
APA	A. R. Palla.,M. Ravichandran.,Y. X. Wang.,L. Alexandrova.,A. V. Yang.,...&H. M. Blau.(2021).Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength.Science.
MLA	A. R. Palla,et al."Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength".Science (2021).