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–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.

Disrupted macrophage metabolic reprogramming in aged soleus muscle during early recovery following disuse atrophy

“…Wilcoxon rank-sum test was used to rank genes and determine significance for GSEA and boxplot analysis. Statistical significance is p < 0.05 to stimulate myogenic precursor cell function and aide in muscle regrowth and regeneration (Dort et al, 2019;Ho et al, 2017;Palla et al, 2021;Shen et al, 2006). Within hours of a stimuli, neutrophils infiltrate the tissue to mount an immune response which serves to aid in pro-inflammatory macrophage recruitment (Arnold et al, 2007).…”

Stem cell-free therapy for glaucoma to preserve vision

“…PGE2 has been reported to increase self-renewal and proliferation of stem cells 40 . Recently Pala et al discovered the interesting role of PGE2 in restoring muscle function in aging induced animals in addition to augmenting stem cell function 54,55 . PGE2 has been also reported to increase hematopoietic 56 and bone homeostasis 57 and aid in liver regeneration 58 .…”

Dynamic Aging: Channeled Through Microenvironment

“…A recent study found that prostaglandin-degrading enzyme 15-PGDH elevated in aged mice and contributed to sarcopenia. Pharmaceutically inhibition of 15-PGDH increased muscle mass and strength in old mice by increasing PGE2 levels, also improved mitochondrial function and autophagy by decreasing TGF-beta and ubiquitin- proteasome pathways ( Palla et al, 2021 ). Another new finding reported that in aging macrophages and microglia, the lipid messenger prostaglandin E2 (PGE2), a major circulating modulator of inflammation, could reduce glucose flux and mitochondrial respiration through its EP2 receptor.…”