Regulation of eicosanoid signaling lipids to improve skeletal muscle function and increase healthspan during aging

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PROJECT SUMMARY Age-related muscle atrophy, or sarcopenia, affects 15% of the elderly, diminishing quality of life and increasing morbidity and mortality. During aging, skeletal muscles undergo structural and functional alterations as a result of multiple dysregulated pathways. Due to this multifactorial etiology, untangling the causal molecular pathways in order to identify therapeutic targets to prevent, delay or reverse sarcopenia has proven challenging. Our goal is to elucidate novel causal mechanisms of sarcopenia and use this knowledge to improve aged muscle function. Our preliminary data has revealed a reduction in specific lipid prostaglandin metabolites in aged muscles. We recently discovered that this reduction resulted from catabolism by 15-hydroxyprostaglandin dehydrogenase (15- PGDH), the prostaglandin degrading enzyme, which is markedly increased in aged mouse and human muscles. To determine the role of 15-PGDH in sarcopenia, we overexpressed the enzyme in young muscles, observed a predicted reduction in PGE2 and PGD2 levels, which was accompanied by an unexpectedly marked decrease in muscle mass and function, mimicking key features of sarcopenia. The discovery of 15-PGDH upregulation and concomitant decrease in prostaglandin levels in aged muscle forms the basis for the proposed research and enables targeted molecular and functional studies previously not possible. We hypothesize that during aging, senescent and inflammatory cells accumulate in the muscle microenvironment and express 15-PGDH, which degrades PGE2 and PGD2, and causes muscle wasting. We further hypothesize that inhibition of 15-PGDH in aged muscles will increase PGE2 and PGD2 lipid metabolites and augment muscle mass and strength. In the proposed research we aim to (i) elucidate the role of the lipid prostaglandin PGE2 and PGD2 metabolites in skeletal muscle homeostasis, (ii) identify the cell source of 15-PGDH and prostaglandin dysregulation in aged muscle, and (iii) restore muscle function and mass of aged muscles by inhibiting the catabolic enzyme, 15- PGDH. This work will benefit from techniques we have previously developed to quantify prostaglandin levels: mass-spectrometric-based lipid profiling and muscle force assessments over time using non-invasive methods. Further, we will capitalize on a single-cell technology we recently optimized for the study of skeletal muscle tissue, multiplexed tissue imaging (also known as CODEX, CO-Detection by indEXing), that resolves up to 60 markers simultaneously in single tissue sections. CODEX will enable a determination of whether senescent cells comprise a cell source of 15-PGDH and resolution of spatial relationships among the diverse cell types in aged muscles. Together, these studies will provide insights into a novel dysregulated pathway, lipid prostaglandin signaling in aged muscles, and determine if inhibiting PGE2 and PGD2 catabolism mediated by 15-PGDH, aug- ments aged muscle mass and function. This research will identify lipid signaling mechanisms that go awry in aging and inform therapeutic strategies for sarcopenia.