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.

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.

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.

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 …