iPLA₂β: A novel store-operated calcium entry modulator contributing to muscle dysfunction during denervation

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 A₂β (iPLA₂β) as a novel regulator of store-operated calcium ion (Ca²⁺) entry (SOCE), a critical process for maintaining Ca²⁺ homeostasis via stromal interaction molecule 1 (STIM1) and Orai1 coupling in skeletal muscle. Using muscle-specific iPLA₂β knockout (miPLA₂βKO) mice, we show that iPLA₂β interacts with STIM1-Orai1 coupling to modulate SOCE. Denervation elevates iPLA₂β, hyperactivating SOCE and causing Ca²⁺ overload through oxidative impairment of regulators such as SERCA. iPLA₂β deletion normalizes SOCE, preserves Ca²⁺ homeostasis, and protects against denervation-induced muscle mass (5%) and strength loss (50%). These findings reveal that iPLA₂β may be a critical link between oxidative stress and Ca²⁺ dysregulation and a promising target for mitigating muscle dysfunction during denervation.