Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice.
Bottom Line: By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres.Treatment of mice with both agents results in improved muscle regeneration and increased force.Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.
Affiliation: Biozentrum, University of Basel, Switzerland. firstname.lastname@example.orgShow MeSH
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Mentions: We have recently shown that oral application of the pharmacological apoptosis inhibitor omigapil to dyW/dyW mice ameliorates MDC1A pathology (Erb et al, 2009). Based on the finding that transgenic expression of Bcl2 increased the therapeutic effect of mini-agrin, we next tested whether the combination of mini-agrin and systemic application of omigapil would be of benefit. To this end, dyW/mag mice were treated with a daily dose of 0.1 mg/kg omigapil starting at the age of 15 days. The first week of treatment, omigapil was injected into the peritoneum followed by oral gavage after weaning. Mice were analysed at the age of 12 weeks. Visual inspection of H & E-stained cross-sections from triceps muscle did not reveal a striking difference between omigapil- (dyW/mag-omigapil) and vehicle- (dyW/mag-vehicle) treated dyW/mag mice (Fig 7A). Quantitative assessment of changes showed, however, lowered creatine kinase (CK) levels in the blood (Fig 7B), normalized muscle fibre size distribution (Fig 7C), a trend to increasing the mean fibre size (Fig 7D) and to enlarging muscle area in dyW/mag mice (Fig 7E). In addition, omigapil also reduced the muscle fibre loss in dyW/mag mice (Fig 7F). Importantly, many of the functional parameters were significantly improved by omigapil. Those included body weight gain (Fig 7G), locomotive activity in the open-field test (Fig 7H) and grip strength (Fig 7I). However, we could not detect a difference in the overall survival (Fig 7J). Together, treatment of dyW/mag mice with omigapil further improved several of the disease parameters but did not affect survival.
Affiliation: Biozentrum, University of Basel, Switzerland. email@example.com