Shim and colleagues develop DLMEH, a metabolically stabilized D-leucine prodrug that bypasses first-pass catabolism. DLMEH activates Sestrin2-dependent mTORC1 signaling, restoring muscle protein synthesis in dexamethasone-induced atrophy. In rat models, DLMEH preserves muscle mass, strength, and endurance superior to L-leucine, supporting DLMEH as a first-in-class candidate for sarcopenia.