PMID:20610565

Citation	Lovett, FA, Cosgrove, RA, Gonzalez, I and Pell, JM (2010) Essential role for p38alpha MAPK but not p38gamma MAPK in Igf2 expression and myoblast differentiation. Endocrinology 151:4368-80
Abstract	The muscle satellite cell is established as the major stem cell contributing to fiber growth and repair. p38 MAPK signaling is essential for myoblast differentiation and in particular for up-regulation of promyogenic Igf2 expression. p38 exists as four isoforms (alpha, beta, gamma, and delta), of which p38gamma is uniquely abundant in muscle. The aim of this study was to characterize p38 isoform expression and importance (using shRNA knockdown; demonstrated via both reduced protein and kinase activities) during myoblast differentiation. p38alpha and -gamma mRNA levels were most abundant in differentiating C2 cells with low/negligible contributions from p38beta and -delta, respectively. Increased phosphorylation of p38alpha and -gamma occurred during differentiation but via different mechanisms: p38alpha protein levels remained constant, whereas total p38gamma levels increased. Following shRNA knockdown of p38alpha, myoblast differentiation was dramatically inhibited [reduced myosin heavy chain (MHC), myogenin, pAkt protein levels]; significantly, Igf2 mRNA levels and promoter-reporter activities decreased. In contrast, knockdown of p38gamma induced a transient increase in both myogenin and MHC protein levels with no effect on Igf2 mRNA levels or promoter-reporter activity. Knockdown of p38alpha/beta markedly increased but that of p38gamma decreased caspase 3 activity, suggesting opposite actions on apoptosis. p38gamma was initially proposed to have a promyogenic function; however, p38gamma overexpression could not rescue reduced myoblast differentiation following p38alpha/beta inhibition. Therefore, p38alpha is essential for myoblast differentiation, and part of its action is to convert signals that indicate cell density into promyogenic gene expression in the form of the key peptide, IGF-II; p38gamma has a minor, yet opposing antimyogenic, function.
Links	PubMed Online version:10.1210/en.2010-0209
Keywords	Animals; Blotting, Northern; Blotting, Western; Caspase 3/metabolism; Cell Differentiation/drug effects; Cell Differentiation/genetics; Cell Differentiation/physiology; Cells, Cultured; Enzyme Inhibitors/pharmacology; Gene Expression Regulation; Gene Knockout Techniques; Imidazoles/pharmacology; Insulin-Like Growth Factor II/genetics; Insulin-Like Growth Factor II/pharmacology; Luciferases/genetics; Luciferases/metabolism; Mice; Mitogen-Activated Protein Kinase 12/genetics; Mitogen-Activated Protein Kinase 12/metabolism; Mitogen-Activated Protein Kinase 14/genetics; Mitogen-Activated Protein Kinase 14/metabolism; Myogenin/metabolism; Myosin Heavy Chains/metabolism; Promoter Regions, Genetic/genetics; Pyridines/pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Satellite Cells, Skeletal Muscle/cytology; Satellite Cells, Skeletal Muscle/drug effects; Satellite Cells, Skeletal Muscle/metabolism; Transfection
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:MK14	acts_upstream_of_or_within	GO:0014835: myoblast differentiation involved in skeletal muscle regeneration	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(CL:0000056)	Seeded From UniProt	complete

References

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