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 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.
Cassano
Marco
M
Translational Cardiomyology, Stem Cell Institute Leuven, KULeuven, Leuven, Belgium.
Biressi
Stefano
S
Finan
Amanda
A
Benedetti
Laura
L
Omes
Claudia
C
Boratto
Renata
R
Martin
Frank
F
Allegretti
Marcello
M
Broccoli
Vania
V
Cusella De Angelis
Gabriella
G
Comoglio
Paolo M
PM
Basilico
Cristina
C
Torrente
Yvan
Y
Michieli
Paolo
P
Cossu
Giulio
G
Sampaolesi
Maurilio
M
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
D011994:Recombinant Proteins; D049031:Sarcoglycans; C533045:magic-factor 1 protein, mouse; D019859:Proto-Oncogene Proteins c-met
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