iPLA2β: A novel store-operated calcium entry modulator contributing to muscle dysfunction during denervation
TL;DR
iPLA2β deletion normalizes SOCE, preserves Ca2+ homeostasis, and protects against denervation-induced muscle mass and strength loss, revealing that iPLA2β may be a critical link between oxidative stress and Ca2+ dysregulation and a promising target for mitigating muscle dysfunction during denervation.
Abstract
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.