Restoration of Capacity to Build Muscle Strength in Geriatric Mice by Inhibition of the Gerozyme 15-Prostaglandin Dehydrogenase

Loss of skeletal muscle mass and strength with age drives sarcopenia, a syndrome affecting >100 million people worldwide that leads to loss of mobility, independence, and increased mortality. Mechanical overload induces hypertrophy in young muscle, but this response is markedly attenuated with age - a poorly understood phenomenon termed anabolic resistance. Here we test whether impaired paracrine communication between myofibers and their niche underlies this loss of plasticity in geriatric mice. In aged muscle, pharmacological inhibition of 15-PGDH restores prostaglandin E2 (PGE2) bioavailability and rescues the anabolic response, increasing muscle growth and contractile strength. Single-nuclei RNA-seq revealed a paracrine circuit: PGE2 drives IGF1 synthesis in type IIb myonuclei, which signals to stromal, myogenic, myonuclear, and immune cells. Blocking IGF1 receptor signaling abolished these gains, placing PGE2 upstream of an IGF1-mediated circuit that coordinates multicellular hypertrophy. Thus, 15-PGDH inhibition is a pharmacological strategy to overcome the anabolic resistance and rebuild muscle in aging.