Xu_2026_Sci.Adv_12_eaed1646

Sarcopenia, the age-related loss of skeletal muscle mass and strength, is a major cause of frailty and disability, with neuromuscular denervation as a key contributor. Bioactive lipid mediators, including lipid hydroperoxides and oxylipins, contribute to denervation-induced muscle atrophy and dysfunction. Here, we identify calcium-independent phospholipase A(2)beta (iPLA(2)beta) as a novel regulator of store-operated calcium ion (Ca(2+)) entry (SOCE), a critical process for maintaining Ca(2+) homeostasis via stromal interaction molecule 1 (STIM1) and Orai1 coupling in skeletal muscle. Using muscle-specific iPLA(2)beta knockout (miPLA(2)betaKO) mice, we show that iPLA(2)beta interacts with STIM1-Orai1 coupling to modulate SOCE. Denervation elevates iPLA(2)beta, hyperactivating SOCE and causing Ca(2+) overload through oxidative impairment of regulators such as SERCA. iPLA(2)beta deletion normalizes SOCE, preserves Ca(2+) homeostasis, and protects against denervation-induced muscle mass (5%) and strength loss (50%). These findings reveal that iPLA(2)beta may be a critical link between oxidative stress and Ca(2+) dysregulation and a promising target for mitigating muscle dysfunction during denervation.