title: Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice.
abstract: Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin ('mini-agrin') or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. 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.
authors.affiliation: Biozentrum, University of Basel, Switzerland. markus-a.ruegg@unibas.ch
authors.forename: Sarina
authors.initials: S
authors.lastname: Meinen
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Raphael
authors.initials: R
authors.lastname: Thurnherr
authors.forename: Michael
authors.initials: M
authors.lastname: Erb
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
mesh_terms: D018171:Agrin / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006651:Histocytochemistry; D007150:Immunohistochemistry; D007797:Laminin / Q000172:deficiency*; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000473:pathology; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology*; D009465:Neuromuscular Agents / Q000008:administration & dosage*; D010082:Oxepins / Q000008:administration & dosage*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D012376:Rodent Diseases / Q000188:drug therapy / Q000473:pathology; D016019:Survival Analysis
chemical_list: D018171:Agrin; D007797:Laminin; D009465:Neuromuscular Agents; D010082:Oxepins; D019253:Proto-Oncogene Proteins c-bcl-2; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; C102645:laminin alpha 2