Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anilides / pharmacology
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Animals
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Caffeine / pharmacology
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Calcium Channels / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Group VI Phospholipases A2
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Ion Transport / drug effects
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Manganese / metabolism
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Melitten / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Inbred mdx
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Models, Biological
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / enzymology*
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / enzymology*
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Muscular Dystrophy, Animal / chemically induced*
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Naphthalenes / pharmacology
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Phospholipases A / antagonists & inhibitors
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Phospholipases A / metabolism*
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Phospholipases A2
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Potassium Chloride / metabolism
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Pyrones / pharmacology
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
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Thiadiazoles / pharmacology
Substances
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4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide
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Anilides
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Calcium Channels
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Naphthalenes
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Pyrones
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Thiadiazoles
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Melitten
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Caffeine
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Manganese
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Potassium Chloride
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6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one
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Phospholipases A
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Group VI Phospholipases A2
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Phospholipases A2
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Pla2g6 protein, mouse
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Sarcoplasmic Reticulum Calcium-Transporting ATPases