Comparison between gentamycin and exon skipping treatments to restore ryanodine receptor subtype 2 functions in mdx mouse duodenum myocytes
European Journal of Pharmacology. 2010-02-01; 628(1-3): 36-41
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1. Eur J Pharmacol. 2010 Feb 25;628(1-3):36-41. doi: 10.1016/j.ejphar.2009.11.034.
Epub 2009 Nov 26.
Comparison between gentamycin and exon skipping treatments to restore ryanodine
receptor subtype 2 functions in mdx mouse duodenum myocytes.
Dabertrand F(1), Mironneau J, Henaff M, Macrez N, Morel JL.
(1)Department of Pharmacology, UVM College of Medicine, B-333 Given Building,
Burlington, VT 05405-0068, USA.
In Duchenne muscular dystrophy, a stop-codon mutation in the dystrophin gene
induces an impairment of skeletal and smooth muscles contraction. In duodenum
from mdx mouse, the disease model, the decrease of contractility was linked with
the decrease of calcium signals encoded by ryanodine receptor subtype 2.
Aminoglycoside and antisense oligonucleotide strategies were investigated to
restore calcium signalling in the mdx mouse. Mdx mice were treated by
intraperitoneal injection of gentamycin or 2-O-methyl antisense ribonucleotide
directed against exon 23 of dystrophin for 2 weeks. The efficiency of both
therapeutic strategies was determined by the level of dystrophin protein
expression. The physiological effects of both treatments on ryanodine receptor
expression and function were followed by RT-PCR, western blot and calcium
measurements. Fourteen days after injection of gentamycin or anti-dystrophin
antisense, the expression of dystrophin was recovered in skeletal muscle from
treated mdx mice. In duodenum cells, RT-PCR and western blot indicated that the
expression of ryanodine receptor subtype 2 was similar in treated mice than in
control mice in association with the recovery of caffeine-induced Ca(2+)
response. No significant difference was observed in the ryanodine subtype
3-dependent spontaneous Ca(2+) oscillations in untreated and treated mice.
Conclusions – these results may help to explain the efficiency of aminoglycoside
and anti-dystrophin antisense treatments in smooth muscle. Both treatments could
be an interesting therapeutic option to restore smooth muscle contraction in
patients with Duchenne muscular dystrophy.
PMID: 19944091 [Indexed for MEDLINE]