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: Besides its function in stabilizing muscle fibres during contraction, LM-211 has also been shown to be important for the successful regeneration of muscle (Bentzinger et al, 2005; Kuang et al, 1999). In addition, regeneration is improved in dyW/mag mice (Meinen et al, 2007). Regenerating muscle fibres transiently express the developmental form of myosin heavy chain (dMyHC; Novocastra, NCL-MHCd) and newly regenerated fibres have their nuclei in the centre and not in the periphery. Thus, the number of dMyHC-positive and centrally nucleated fibres (CNF) is a measure of ongoing and successful regeneration. To assess the role of apoptosis inhibition in the regeneration process, we first counted the number of CNF in the different mouse models. As shown earlier, the number of CNF was increased in dyW/dyW mice due to ongoing muscle degeneration when compared to WT controls (Fig 4A). Expression of Bcl2 resulted in a further threefold increase in the number of CNF, suggesting that regeneration of muscle fibres is more effective. Similarly, the number of CNF was increased in dyW/mag mice compared to dyW/dyW but was lower than in dyW/Bcl mice. This finding is consistent with the previous interpretation that mini-agrin enables successful regeneration but primarily prevents muscle degeneration by its linking of the basement membrane to α-dystroglycan (Moll et al, 2001). Interestingly, expression of both Bcl2 and mini-agrin resulted in a further increase of the number of CNF in 12- and 16-week-old mice compared to dyW/mag mice. To test for ongoing regeneration, we also stained for dMyHC. As with CNF, the number of dMyHC-positive fibres in triceps muscle was several fold higher in dyW/Bcl than in dyW/dyW mice and the effect of Bcl2 was also seen when combined with mini-agrin (Fig 4B and C).
Affiliation: Biozentrum, University of Basel, Switzerland. email@example.com