title: Local expression of mIgf-1 modulates ubiquitin, caspase and CDK5 expression in skeletal muscle of an ALS mouse model.
abstract: OBJECTIVE
  The functional connection between muscle and nerve is often altered in several neuromuscular diseases, including amyotrophic lateral sclerosis (ALS). Knowledge about the molecular and cellular mechanisms involved in the restorative reactions is important to our understanding of the processes involved in neuromuscular maintenance. We previously reported that muscle-restricted expression of a localized Igf-1 isoform maintained muscle integrity, stabilized neuromuscular junctions, reduced inflammation in the spinal cord and enhanced motor neuronal survival in SOD(G93A) mice, delaying the onset and progression of the disease. In this study, we analysed potential molecular pathways that are modulated by mIgf-1 to counteract muscle wasting and to preserve motor neurons activity.
  
  
  METHODS
  We performed molecular and morphologic analysis to address the specific proposed questions.
  
  
  CONCLUSIONS
  Ubiquitin expression and caspase activity resulted markedly increased in SOD(G93A) muscle but maintained at very low levels in the SOD(G93A) x MLC/mIgf-1 (SOD(G93A)/mIgf-1) transgenic muscle. In addition, CDK5 expression, a serine-threonine protein kinase that has been implicated in a number of physiologic processes in nerve and muscle cells, was reduced in SOD(G93A) muscle but increased in SOD(G93A)/mIgf-1 muscle. Notably, while the toxic p25 protein accumulated in SOD(G93A) muscle, no accumulation was evident in the SOD(G93A)/mIgf-1 muscle. The maintenance of muscle phenotype was also associated with maintenance of a normal peripheral nerve, and a greater number of myelinated axons.
  
  
  CONCLUSIONS
  These observations offer novel insights into the role of mIgf-1 in the attenuation of muscle wasting in the mouse model of ALS disease.
authors.affiliation: Department of Histology and Medical Embryology, Centro Eccellenza BEMM and IIM, University of Rome La Sapienza, Via A. Scarpa, 14 Rome 00161, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Dobrowolny
authors.forename: Michela
authors.initials: M
authors.lastname: Aucello
authors.forename: Mario
authors.initials: M
authors.lastname: Molinaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D051360:Cyclin-Dependent Kinase 5; D020169:Caspases