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

Area of Science:

• Muscle physiology
• Cellular biology
• Biochemistry

Background:

• Sarcopenia, linked to aging and neuromuscular denervation, causes frailty and disability.
• Bioactive lipids, including oxylipins, exacerbate denervation-induced muscle atrophy and dysfunction.
• Calcium homeostasis is crucial for skeletal muscle function.

Purpose of the Study:

• To identify novel regulators of store-operated calcium ion (Ca2+) entry (SOCE) in skeletal muscle.
• To investigate the role of calcium-independent phospholipase A2β (iPLA2β) in denervation-induced muscle dysfunction.
• To explore iPLA2β as a potential therapeutic target for sarcopenia.

Main Methods:

• Utilized muscle-specific iPLA2β knockout (miPLA2βKO) mice.
• Examined the interaction between iPLA2β and STIM1-Orai1 coupling in modulating SOCE.
• Assessed Ca2+ homeostasis, muscle mass, and muscle strength following denervation.

Main Results:

• iPLA2β was identified as a novel regulator of SOCE in skeletal muscle.
• Denervation led to elevated iPLA2β, hyperactivated SOCE, and Ca2+ overload.
• miPLA2βKO mice showed normalized SOCE, preserved Ca2+ homeostasis, and significantly reduced muscle mass and strength loss.
• iPLA2β deletion protected against denervation-induced muscle atrophy and weakness.

Conclusions:

• iPLA2β is a critical link between oxidative stress and Ca2+ dysregulation in denervated muscle.
• iPLA2β modulates SOCE through interaction with STIM1-Orai1.
• Targeting iPLA2β may offer a promising strategy to mitigate muscle dysfunction and sarcopenia.