Pre-clinical study of 21 approved drugs in the mdx mouse.

Duchenne muscular dystrophy, a genetic disease caused by the absence of functional dystrophin, remains without adequate treatment. Although great hopes are attached to gene and cell therapies, identification of active small molecules remains a valid option for new treatments. We have studied the effect of 20 approved pharmaceutical compounds on the muscles of dystrophin-deficient mdx5Cv mice.

Diaphragm tension reduced in dystrophic mice by an oxidant, hypochlorous acid.

In dystrophin-deficient skeletal muscle cells, in which Ca2+ homeostasis is disrupted and reactive oxygen species production is increased, we hypothesized that hypochlorous acid (HOCl), a strong H2O2-related free radical, damages contractile proteins and the sarcoplasmic reticulum. The aim of the present study was to investigate the effects of exposure to oxidative stress, generated by applying HOCl (100 micromol/L and 1 mmol/L), on the contractile function and sarcoplasmic reticulum properties of dystrophic mice. Experiments were performed on diaphragm muscle, which is severely affected in the mdx mouse, and the results were compared with those obtained in healthy (non-dystrophic) mice.

Increased Ca2+ storage capacity of the skeletal muscle sarcoplasmic reticulum of transgenic mice over-expressing membrane bound calcium binding protein junctate.

Junctate is an integral sarco(endo)plasmic reticulum protein expressed in many tissues including heart and skeletal muscle. Because of its localization and biochemical characteristics, junctate is deemed to participate in the regulation of the intracellular Ca2+ concentration. However, its physiological function in muscle cells has not been investigated yet.

Fetal muscle-derived cells can repair dystrophic muscles in mdx mice.

We have previously reported that CD34(+) cells purified from mouse fetal muscles can differentiate into skeletal muscle in vitro and in vivo when injected into muscle tissue of dystrophic mdx mice. In this study, we investigate the ability of such donor cells to restore dystrophin expression, and to improve the functional muscle capacity of the extensor digitorum longus muscle (EDL) of mdx mice. For this purpose green fluorescent-positive fetal GFP(+)/CD34(+) cells or desmin(+)/(-)LacZ/CD34(+) cells were transplanted into irradiated or non-irradiated mdx EDL muscle.

Greater susceptibility of the sarcoplasmic reticulum to H2O2 injuries in diaphragm muscle from mdx mice.

The aim of the present study was to investigate the direct effects of a reactive oxygen species, H(2)O(2), on the contractile function and sarcoplasmic reticulum properties of dystrophin-deficient diaphragm using chemically skinned fibers and sarcoplasmic reticulum vesicle preparations. The results obtained using Triton X-100-skinned fibers demonstrate that exposure to 1 mM H(2)O(2) had similar effects on the maximal Ca(2+)-activated tension and on the Ca(2+) sensitivity of the contractile apparatus of diaphragm fibers in Bl10 and mdx mice. The effects of H(2)O(2) were also assessed on sarcoplasmic reticulum function using saponin-skinned fibers and sarcoplasmic reticulum vesicle preparations.

Sarcoplasmic reticulum function in slow- and fast-twitch skeletal muscles from mdx mice.

The aim of the present study was to establish whether alterations in sarcoplasmic reticulum function are involved in the abnormal Ca(2+) homeostasis of skeletal muscle in mice with muscular dystrophy ( mdx). The properties of the sarcoplasmic reticulum and contractile proteins of fast- and slow-twitch muscles were therefore investigated in chemically skinned fibres isolated from the extensor digitorum longus (EDL) and soleus muscles of normal (C57BL/10) and mdx mice at 4 and 11 weeks of development. Sarcoplasmic reticulum Ca(2+) uptake, estimated by the Ca(2+) release following exposure to caffeine, was significantly slower in mdx mice, while the maximal Ca(2+) quantity did not differ in either type of skeletal muscle at either stage of development.

IP(3)-induced tension and IP(3)-receptor expression in rat soleus muscle during postnatal development.

The present study was designed to examine whether changes in Ca(2+) release by inositol-1,4,5-trisphosphate (IP(3)) in 8-, 15-, and 30-day-old rat skeletal muscles could be associated with the expression of IP(3) receptors. Experiments were conducted in slow-twitch muscle in which both IP(3)-induced Ca(2+) release and IP(3)-receptor (IP(3)R) expression have been shown to be larger than in fast-twitch muscle. In saponin-skinned fibers, IP(3) induced transient contractile responses in which the amplitude was dependent on the Ca(2+)-loading period with the maximal IP(3) contracture being at 20 min of loading.