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First published online 22 August 2006
doi: 10.1242/jcs.03184

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Ca²⁺-independent phospholipase A₂ enhances store-operated Ca²⁺ entry in dystrophic skeletal muscle fibers

Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva 4, Switzerland

^* Author for correspondence (e-mail: Urs.Ruegg{at}pharm.unige.ch)

Accepted 18 July 2006

Duchenne muscular dystrophy is caused by deficiency of dystrophin and leads to progressive weakness. It has been proposed that the muscle degeneration occurring in this disease is caused by increased Ca²⁺ influx due to enhanced activity of cationic channels that are activated either by stretch of the plasma membrane (stretch-activated channels) or by Ca²⁺-store depletion (store-operated channels). Using both cytosolic Ca²⁺ measurements with Fura-2 and the manganese quench method, we show here that store-operated Ca²⁺ entry is greatly enhanced in dystrophic skeletal flexor digitorum brevis fibers isolated from mdx^5cv mice, a mouse model of Duchenne muscular dystrophy. Moreover, we show for the first time that store-operated Ca²⁺ entry in these fibers is under the control of the Ca²⁺-independent phospholipase A₂ and that the exaggerated Ca²⁺ influx can be completely attenuated by inhibitors of this enzyme. Enhanced store-operated Ca²⁺ entry in dystrophic fibers is likely to be due to a near twofold overexpression of Ca²⁺-independent phospholipase A₂. The Ca²⁺-independent phospholipase A₂ pathway therefore appears as an attractive target to reduce excessive Ca²⁺ influx and subsequent degeneration occurring in dystrophic fibers.

Key words: Dystrophic skeletal muscle fibers, Store-operated channel, Ca²⁺-independent phospholipase A₂

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