Pharmacological control of cellular calcium handling in dystrophic skeletal muscle.
Duchenne muscular dystrophy arises due to the lack of the cytoskeletal protein dystrophin. In Duchenne muscular dystrophy muscle, the lack of dystrophin is accompanied by alterations in the dystrophin-glycoprotein complex. We and others have found that the absence of dystrophin in cells of the Duchenne muscular dystrophy animal model, the mdx mouse, leads to elevated Ca(2+) influx and cytosolic Ca(2+) concentrations when exposed to stress. We have also shown that alpha-methylprednisolone, the only drug used successfully in the therapy of Duchenne muscular dystrophy, and creatine lowered cytosolic Ca(2+) levels in mdx myotubes. It is likely that chronic elevation of [Ca(2+)] in the cytosol in response to stress is an initiating event for apoptosis and/or necrosis in Duchenne muscular dystrophy or mdx muscle and that alterations in mitochondrial function and metabolism are involved. Other cellular signalling pathways (e.g. nitric oxide) might also be affected.
Ruegg
Urs T
UT
Pharmacology Group, School of Pharmacy, University of Lausanne/BEP, CH-1015 Lausanne, Switzerland. urs.ruegg@dpharm.unil.ch
Nicolas-Métral
Valérie
V
Challet
Corinne
C
Bernard-Hélary
Katy
K
Dorchies
Olivier M
OM
Wagner
Stéphanie
S
Buetler
Timo M
TM
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D003401:Creatine / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency*; D005938:Glucocorticoids / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D018101:Mice, Inbred mdx; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism; D009336:Necrosis; D015398:Signal Transduction / Q000187:drug effects
D015220:Calcium Channels; D016189:Dystrophin; D005938:Glucocorticoids; D003401:Creatine; D002118:Calcium; D008775:Methylprednisolone