The decrease of expression of ryanodine receptor sub-type 2 is reversed by gentamycin sulphate in vascular myocytes from mdx mice.
The mdx mouse, a model of the human Duchenne muscular dystrophy, displays impaired contractile function in skeletal, cardiac and smooth muscles. We explored the possibility that ryanodine receptor (RYR) expression could be altered in vascular muscle. The three RYR sub-types were expressed in portal vein myocytes. As observed through mRNA and protein levels, RYR2 expression was strongly decreased in mdx myocytes, whereas RYR3 and RYR1 expression were unaltered. The use of antisense oligonucleotide directed against RYR sub-types indicated that caffeine-induced Ca(2+) response and Ca(2+) spark frequency depended on RYR2 and RYR1. In mdx mice, caffeine-induced Ca(2+) responses were decreased in both amplitude and maximal rate of rise, and the frequency of Ca(2+) sparks was also strongly decreased. The gentamycin treatment was able to increase both the expression of RYR2 and the caffeine-induced Ca(2+) response to the same level as that observed in wild-type mice. Taken together, these results confirm that both RYR1 and RYR2 are required for vascular Ca(2+) signalling and indicate that inhibition of RYR2 expression may account for the decreased Ca(2+) release from the SR in mdx vascular myocytes. Finally, we suggest that gentamycin can restore the Ca(2+) signalling in smooth muscle from mdx mice by increasing RYR2 and dystrophin expression. These results may help explain the reduced efficacy of contraction in vascular myocytes of mdx mice and Duchenne muscular dystrophy-afflicted patients. Gentamycin treatment could be a good therapeutic tool to restore the vascular function.
Morel
Jean-Luc
JL
Université de Bordeaux, CNRS, Centre Neurosciences Intégratives et Cognitives, Unité Mixte de Recherche, Talence Cedex, France. jl.morel@cnic.u-bordeaux1.fr
Dabertrand
Fabrice
F
Fritz
Nicolas
N
Henaff
Morgana
M
Mironneau
Jean
J
Macrez
Nathalie
N
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D016189:Dystrophin / Q000096:biosynthesis; D005786:Gene Expression Regulation; D005839:Gentamicins / Q000494:pharmacology*; D051379:Mice; D018101:Mice, Inbred mdx; D032342:Muscle Cells / Q000166:cytology*; D009130:Muscle, Smooth / Q000166:cytology*; D012333:RNA, Messenger / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis*; D015398:Signal Transduction; D013431:Sulfates / Q000494:pharmacology*
D016189:Dystrophin; D005839:Gentamicins; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D013431:Sulfates; D002118:Calcium