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Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis

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 ran...

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Autores principales: Cassano, Marco, Biressi, Stefano, Finan, Amanda, Benedetti, Laura, Omes, Claudia, Boratto, Renata, Martin, Frank, Allegretti, Marcello, Broccoli, Vania, Cusella De Angelis, Gabriella, Comoglio, Paolo M., Basilico, Cristina, Torrente, Yvan, Michieli, Paolo, Cossu, Giulio, Sampaolesi, Maurilio
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528937/
https://www.ncbi.nlm.nih.gov/pubmed/18795097
http://dx.doi.org/10.1371/journal.pone.0003223
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author Cassano, Marco
Biressi, Stefano
Finan, Amanda
Benedetti, Laura
Omes, Claudia
Boratto, Renata
Martin, Frank
Allegretti, Marcello
Broccoli, Vania
Cusella De Angelis, Gabriella
Comoglio, Paolo M.
Basilico, Cristina
Torrente, Yvan
Michieli, Paolo
Cossu, Giulio
Sampaolesi, Maurilio
author_facet Cassano, Marco
Biressi, Stefano
Finan, Amanda
Benedetti, Laura
Omes, Claudia
Boratto, Renata
Martin, Frank
Allegretti, Marcello
Broccoli, Vania
Cusella De Angelis, Gabriella
Comoglio, Paolo M.
Basilico, Cristina
Torrente, Yvan
Michieli, Paolo
Cossu, Giulio
Sampaolesi, Maurilio
author_sort Cassano, Marco
collection PubMed
description 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 α-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/SIGNIFICANCE: 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.
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spelling pubmed-25289372008-09-16 Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis Cassano, Marco Biressi, Stefano Finan, Amanda Benedetti, Laura Omes, Claudia Boratto, Renata Martin, Frank Allegretti, Marcello Broccoli, Vania Cusella De Angelis, Gabriella Comoglio, Paolo M. Basilico, Cristina Torrente, Yvan Michieli, Paolo Cossu, Giulio Sampaolesi, Maurilio PLoS One Research Article 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 α-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/SIGNIFICANCE: 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. Public Library of Science 2008-09-16 /pmc/articles/PMC2528937/ /pubmed/18795097 http://dx.doi.org/10.1371/journal.pone.0003223 Text en Cassano et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cassano, Marco
Biressi, Stefano
Finan, Amanda
Benedetti, Laura
Omes, Claudia
Boratto, Renata
Martin, Frank
Allegretti, Marcello
Broccoli, Vania
Cusella De Angelis, Gabriella
Comoglio, Paolo M.
Basilico, Cristina
Torrente, Yvan
Michieli, Paolo
Cossu, Giulio
Sampaolesi, Maurilio
Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis
title Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis
title_full Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis
title_fullStr Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis
title_full_unstemmed Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis
title_short Magic-Factor 1, a Partial Agonist of Met, Induces Muscle Hypertrophy by Protecting Myogenic Progenitors from Apoptosis
title_sort magic-factor 1, a partial agonist of met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528937/
https://www.ncbi.nlm.nih.gov/pubmed/18795097
http://dx.doi.org/10.1371/journal.pone.0003223
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