Quantitative evaluation of the beneficial effects in the mdx mouse of epigallocatechin gallate, an antioxidant polyphenol from green tea

In two separate previous studies, we reported that subcutaneous (sc) or oral administration of (−)-epigallocatechin-3-gallate (EGCG) limited the development of muscle degeneration of mdx mice, a mild phenotype model for Duchenne muscular dystrophy (DMD). However, it was not possible to conclude which was the more efficient route of EGCG administration because different strains of mdx mice, periods of treatment and methods of assessment were used. In this study, we investigated which administration routes and dosages of EGCG are the most effective for limiting the onset of dystrophic lesions in the same strain of mdx mice and applying the same methods of assessment. Three-week-old mdx mice were injected sc for 5 weeks with either saline or a daily average of 3 or 6 mg/kg EGCG. For comparison, age-matched mdx mice were fed for 5 weeks with either a diet containing 0.1% EGCG or a control diet. The effects of EGCG were assessed quantitatively by determining the activities of serum muscle-derived creatine kinase, isometric contractions of triceps surae muscles, integrated spontaneous locomotor activities, and oxidative stress and fibrosis in selected muscles. Oral administration of 180 mg/kg/day EGCG in the diet was found the most effective for significantly improving several parameters associated with muscular dystrophy. However, the improvements were slightly less than those observed previously for sc injection started immediately after birth. The efficacy of EGCG for limiting the development of dystrophic muscle lesions in mice suggests that EGCG may be of benefit for DMD patients

P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy

open access articleDuchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP–P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target

Magnetic Resonance Imaging

International audienceChapter 2. Magnetic Resonance Imaging 73 Dominique SAPPEY-MARINIER and André BRIGUE

The Ets transcription factor GABP is required for postsynaptic differentiation in vivo

At chemical synapses, neurotransmitter receptors are concentrated in the postsynaptic membrane. During the development of the neuromuscular junction, motor neurons induce aggregation of acetylcholine receptors (AChRs) underneath the nerve terminal by the redistribution of existing AChRs and preferential transcription of the AChR subunit genes in subsynaptic myonuclei. Neural agrin, when expressed in nonsynaptic regions of muscle fibers in vivo, activates both mechanisms resulting in the assembly of a fully functional postsynaptic apparatus. Several lines of evidence indicate that synaptic transcription of AChR genes is primarily dependent on a promoter element called N-box. The Ets-related transcription factor growth-associated binding protein (GABP) binds to this motif and has thus been suggested to regulate synaptic gene expression. Here, we assessed the role of GABP in synaptic gene expression and in the formation of postsynaptic specializations in vivo by perturbing its function during postsynaptic differentiation induced by neural agrin. We find that neural agrin-mediated activation of the AChR epsilon subunit promoter is abolished by the inhibition of GABP function. Importantly, the number of AChR aggregates formed in response to neural agrin was strongly reduced. Moreover, aggregates of acetylcholine esterase and utrophin, two additional components of the postsynaptic apparatus, were also reduced. Together, these results are the first direct in vivo evidence that GABP regulates synapse-specific gene expression at the neuromuscular junction and that GABP is required for the formation of a functional postsynaptic apparatus

Magnetic Resonance Imaging

International audienceChapter 2. Magnetic Resonance Imaging 73 Dominique SAPPEY-MARINIER and André BRIGUE

Relaxation nucléaire dipolaire dans la molécule de chloroforme 13C1HCl3

The density-matrix theory of relaxation for coupled spin systems in the liquid state has been used to derive the relaxation matrix of an A - X system in a (A - X) Yn molecule. The theory is applied to the results of saturation recovery experiments on the proton lines of 13C 1HCl3 in natural abundance in chloroform. It is also shown that the measurement of proton relaxation time of 12C1HCl 3 in the same sample permits to determine the internal dipole relaxation time of 13C 1HCl3. The rotational correlation time of chloroform is measured to be τc = (1.55 ± 0.15) 10 -12 s at 30 °C.La méthode de la matrice densité pour l'étude de la relaxation nucléaire dans les systèmes couplés est utilisée afin d'établir la matrice relaxation d'un système A — X dans une molécule du type (A - X) Yn d'un échantillon liquide. La théorie est appliquée à l'analyse des résultats d'expériences de saturation sur les raies protoniques de la molécule 13C1HCl3 contenue dans le chloroforme naturel. La détermination du temps de relaxation dipolaire intramoléculaire du proton de 13C1HCl3 est effectuée par comparaison avec le temps de relaxation protonique de 12C 1HCl3 dans le même échantillon. La valeur trouvée pour le temps de corrélation de rotation de la molécule de chloroforme est : τ c = (1,55 ± 0,15) 10-12 s à 30 °C

Magnetic Resonance Imaging

International audienceChapter 2. Magnetic Resonance Imaging 73 Dominique SAPPEY-MARINIER and André BRIGUE