Skeletal muscle myogenesis is regulated by G protein-coupled receptor kinase 2

• Published in: Journal of molecular cell biology 2014-08, Vol.6 (4), p.299-311
• Main Author: Lucia Garcia-Guerra Rocio Vila-Bedmar Marta Carrasco-Rando Marta Cruces-Sande Mercedes Martin Ana Ruiz-Gomez Mar Ruiz-Gomez Margarita Lorenzo Sonia Fernandez-Veledo Federico Mayor Jr. Cristina Murga Iria Nieto-Vazquez
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Differentiation; Cells, Cultured; Drosophila; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; G-Protein-Coupled Receptor Kinase 2 - physiology; G蛋白偶联受体激酶; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Muscle Development - physiology; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Myoblasts - cytology; Myoblasts - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; p38MAPK; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; 丝氨酸/苏氨酸激酶; 体细胞; 偶合; 缺失突变体; 过度表达; 骨骼肌纤维
• ISSN: 1674-2788; 1759-4685
• DOI: 10.1093/jmcb/mju025

G protein-coupled receptor kinase 2 （GRK2） is an important serine/threonine-kinase regulating different membrane receptors and intraceUular proteins. Attenuation of Drosophila Gprk2 in embryos or adult flies induced a defective differentiation of somatic muscles, loss of fibers, and a flightless phenotype. In vertebrates, GRK2 hemizygous mice contained less but more hypertrophied skeletal muscle fibers than wild-type littermates. In C2C12 myoblasts, overexpression of a GRK2 kinase-deficient mutant （K220R） caused precocious differentiation of ceUs into immature myotubes, which were wider in size and contained more fused nuclei, while GRK2 overexpression blunted differentiation. Moreover, p38MAPK and Akt pathways were activated at an earlier stage and to a greater extent in K220R-expressing cells or upon kinase downregulation, while the activation of both kinases was impaired in GRK2-overexpressing cells. The impaired differentiation and fewer fusion events promoted by enhanced GRK2 levels were recapitulated by a p38MAPK mutant, which was able to mimic the inhibitory phosphorylation of p38MAPK by GRK2, whereas the blunted differentiation observed in GRK2-expressing clones was rescued in the presence of a constitutively active upstream stimulator of the p38MAPK pathway. These results suggest that balanced GRK2 function is necessary for a timely and complete myogenic process.