Muscle Injuries Induce a Prostacyclin‐PPARγ/PGC1a‐FAO Spike That Boosts Regeneration

It is well‐known that muscle regeneration declines with aging, and aged muscles undergo degenerative atrophy or sarcopenia. While exercise and acute injury are both known to induce muscle regeneration, the molecular signals that help trigger muscle regeneration have remained unclear. Here, mass spectrometry imaging (MSI) is used to show that injured muscles induce a specific subset of prostanoids during regeneration, including PGG1, PGD2, and the prostacyclin PGI2. The spike in prostacyclin promotes skeletal muscle regeneration via myoblasts, and declines with aging. Mechanistically, the prostacyclin spike promotes a spike in PPARγ/PGC1a signaling, which induces a spike in fatty acid oxidation (FAO) to control myogenesis. LC–MS/MS and MSI further confirm that an early FAO spike is associated with normal regeneration, but muscle FAO became dysregulated during aging. Functional experiments demonstrate that the prostacyclin‐PPARγ/PGC1a‐FAO spike is necessary and sufficient to promote both young and aged muscle regeneration, and that prostacyclin can synergize with PPARγ/PGC1a‐FAO signaling to restore aged muscles’ regeneration and physical function. Given that the post‐injury prostacyclin‐PPARγ‐FAO spike can be modulated pharmacologically and via post‐exercise nutrition, this work has implications for how prostacyclin‐PPARγ‐FAO might be fine‐tuned to promote regeneration and treat muscle diseases of aging. Using mass spectrometry imaging, several prostaglandin lipids and fatty acid oxidation (FAO) intermediates are discovered to be injury‐induced myobolites. Detailed studies in vitro and in vivo reveal that the prostacyclin PGI2‐PPARγ/PGC1a‐FAO axis is a key myobolite pathway that spikes transiently to boost muscle regeneration in young mammals, but declines during aging. These myobolites can be targeted to treat aged muscles.