Embryonic deregulation of muscle stress signaling pathways leads to altered postnatal stem cell behavior and a failure in postnatal muscle growth.
PW1 is a mediator of p53 and TNFalpha signaling pathways previously identified in a screen to isolate muscle stem cell regulators. We generated transgenic mice carrying a C-terminal deleted form of PW1 (DeltaPW1) which blocks p53-mediated cell death and TNFalpha-mediated NFkappaB activation fused to the myogenin promoter. Embryonic/fetal muscle development appears normal during transgene expression, however, postnatal transgenic pups display severe phenotypes including runtism, reduced muscle mass and fiber diameters resembling atrophy. Atrogin-1, a marker of skeletal muscle atrophy, is expressed postnatally in transgenic mice. Electron microscopic analyses of transgenic muscle reveal a marked decrease in quiescent muscle satellite cells suggesting a deregulation of postnatal stem cells. Furthermore, transgenic primary myoblasts show a resistance to the effects of TNFalpha upon differentiation. Taken together, our data support a role for PW1 and related stress pathways in mediating skeletal muscle stem cell behavior which in turn is critical for postnatal muscle growth and homeostasis. In addition, these data reveal that postnatal stem cell behavior is likely specified during early muscle development.
Nicolas
Nathalie
N
Brookdale Department of Molecular, Cell, and Developmental Biology, Mount Sinai Medical School, 1 G. Levy Place, New York, NY 10029, USA.
Marazzi
Giovanna
G
Kelley
Kevin
K
Sassoon
David
D
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002478:Cells, Cultured; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D009133:Muscular Atrophy / Q000196:embryology / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D051741:Kruppel-Like Transcription Factors; D009124:Muscle Proteins; D018008:Myogenin; D016328:NF-kappa B; C097901:Peg3 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D011494:Protein Kinases