Phospholipase A2-derived lysophosphatidylcholine triggers Ca2+ entry in dystrophic skeletal muscle fibers.
Duchenne muscular dystrophy is an inherited disease caused by the absence of dystrophin, a structural protein normally located under the sarcolemma of skeletal muscle fibers. Muscle degeneration occurring in this disease is thought to be partly caused by increased Ca(2+) entry through sarcolemmal cationic channels. Using the Mn(2+) quench method, we show here that Mn(2+) entry triggered by Ca(2+) store depletion but not basal Mn(2+) entry relies on Ca(2+)-independent PLA(2) (iPLA(2)) activity in dystrophic fibers isolated from a murine model of Duchenne muscular dystrophy, the mdx(5cv) mouse. iPLA(2) was found to be localized in the vicinity of the sarcolemma and consistently, the iPLA(2) lipid product lysophosphatidylcholine was found to trigger Ca(2+) entry through sarcolemmal channels, suggesting that it acts as an intracellular messenger responsible for store-operated channels opening in dystrophic fibers. Our results suggest that inhibition of iPLA(2) and lysophospholipid production may be of interest to reduce Ca(2+) entry and subsequent degeneration of dystrophic muscle.
Boittin
François-Xavier
FX
Department of Zoology and Animal Biology, Laboratory of Vascular Cell Physiology, University of Geneva, CH-1211 Geneva 4, Switzerland. Francois.Boittin@unige.ch
Shapovalov
George
G
Hirn
Carole
C
Ruegg
Urs T
UT
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism* / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000473:pathology; D054512:Phospholipases A2, Calcium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012508:Sarcolemma / Q000201:enzymology
D008244:Lysophosphatidylcholines; D016718:Arachidonic Acid; D008345:Manganese; D054512:Phospholipases A2, Calcium-Independent; D002118:Calcium