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

Xu, Hongyang, Bhaskaran, Shylesh, Brown, Jacob, Sousa, Luis Gustavo Oliveira de, Georgescu, Constantin, Duggan, Elizabeth, Kneuper, Kara, Bell, Ashley, Thomason, Jessica, Gamez-Rico, Andy, Hagy, Bo, Tyrrell, Victoria, O’Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460, Humphries, Kenneth and Remmen, Holly Van 2026. iPLA2β: A novel store-operated calcium entry modulator contributing to muscle dysfunction during denervation. Science Advances 12 (29) , eaed1646. 10.1126/sciadv.aed1646

PDF - Published Version Available under License Creative Commons Attribution. Download (1MB)

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2375-2548
Date of First Compliant Deposit:	21 July 2026
Date of Acceptance:	3 June 2026
Last Modified:	21 Jul 2026 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/188370

Actions (repository staff only)

Edit Item