title: Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis.
abstract: BACKGROUND
  Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation.
  
  
  RESULTS
  Magic-Factor 1 (Met-Activating Genetically Improved Chimeric Factor-1 or Magic-F1) is an HGF-derived, engineered protein that contains two Met-binding domains repeated in tandem. It has a reduced affinity for Met and, in contrast to HGF it elicits activation of the AKT but not the ERK signaling pathway. As a result, Magic-F1 is not mitogenic but conserves the ability to promote cell survival. Here we show that Magic-F1 protects myogenic precursors against apoptosis, thus increasing their fusion ability and enhancing muscular differentiation. Electrotransfer of Magic-F1 gene into adult mice promoted muscular hypertrophy and decreased myocyte apoptosis. Magic-F1 transgenic mice displayed constitutive muscular hypertrophy, improved running performance and accelerated muscle regeneration following injury. Crossing of Magic-F1 transgenic mice with alpha-sarcoglycan knock-out mice -a mouse model of muscular dystrophy- or adenovirus-mediated Magic-F1 gene delivery resulted in amelioration of the dystrophic phenotype as measured by both anatomical/histological analysis and functional tests.
  
  
  CONCLUSIONS
  Because of these features Magic-F1 represents a novel molecular tool to counteract muscle wasting in major muscular diseases such as cachexia or muscular dystrophy.
authors.affiliation: Translational Cardiomyology, Stem Cell Institute Leuven, KULeuven, Leuven, Belgium.
authors.forename: Marco
authors.initials: M
authors.lastname: Cassano
authors.forename: Stefano
authors.initials: S
authors.lastname: Biressi
authors.forename: Amanda
authors.initials: A
authors.lastname: Finan
authors.forename: Laura
authors.initials: L
authors.lastname: Benedetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Omes
authors.forename: Renata
authors.initials: R
authors.lastname: Boratto
authors.forename: Frank
authors.initials: F
authors.lastname: Martin
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cusella De Angelis
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Cristina
authors.initials: C
authors.lastname: Basilico
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
authors.forename: Paolo
authors.initials: P
authors.lastname: Michieli
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Maurilio
authors.initials: M
authors.lastname: Sampaolesi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009132:Muscles / Q000293:injuries / Q000473:pathology*; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism*; D049031:Sarcoglycans / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D049031:Sarcoglycans; C533045:magic-factor 1 protein, mouse; D019859:Proto-Oncogene Proteins c-met
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