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. email@example.comShow MeSH
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Mentions: To determine the effect of the transgenes on the muscle pathology, we analysed the fast-twitch foreleg muscle triceps brachii (Fig 1) and the slow-twitch hindleg muscle soleus (Fig 2). The latter becomes progressively paralysed in dyW/dyW mice as a consequence of peripheral nerve demyelination (Kuang et al, 1998b). Haematoxylin & Eosin (H & E; Merck) and Masson's trichrome stainings of triceps muscle of 12- (Fig 1A) and 16-week-old animals (Fig 1B) are shown. They revealed extensive fibrosis and a high proportion of small, rounded fibres in dyW/dyW mice (Fig 1A). Expression of mini-agrin (dyW/mag) largely impeded the replacement of muscle with fibrotic tissue while Bcl2 expression (dyW/Bcl) seemed to increase fibrosis in dyW/dyW muscle (Fig 1A), a finding that was confirmed by quantification of the relative fibrotic area (Fig 1C) and by determining the amount of the collagen-specific amino acid hydroxyproline, which is a measure of fibrosis (Fig S2A of Supporting information). However, co-expression of mini-agrin (dyW/Bcl/mag) eliminated the fibrotic impact of Bcl2 (Fig 1A and C and Fig S2A of Supporting information). The high degree of fibrosis in Bcl2 transgenic dyW/dyW mice coincided with a strong increase in the number of macrophages in triceps of dyW/Bcl mice (Fig S2C and D of Supporting information). Like the fibrosis, inflammation was reduced by the co-expression of mini-agrin. The same histological results were also obtained in the soleus muscle of 12-week-old mice (Fig 2A and B and Fig S2B of Supporting information), indicating that the progressed paralysis of the hindlegs did not affect fibrosis.
Affiliation: Biozentrum, University of Basel, Switzerland. firstname.lastname@example.org