title: Gαi2 signaling promotes skeletal muscle hypertrophy, myoblast differentiation, and muscle regeneration.
abstract: Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor-α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gα(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that Gα(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gα(i2) might represent potential targets for preventing skeletal muscle wasting.
authors: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors: Giulia C
authors: GC
authors: Minetti
authors: Jerome N
authors: JN
authors: Feige
authors: Antonia
authors: A
authors: Rosenstiel
authors: Florian
authors: F
authors: Bombard
authors: Viktor
authors: V
authors: Meier
authors: Annick
authors: A
authors: Werner
authors: Frederic
authors: F
authors: Bassilana
authors: Andreas W
authors: AW
authors: Sailer
authors: Peter
authors: P
authors: Kahle
authors: Christian
authors: C
authors: Lambert
authors: David J
authors: DJ
authors: Glass
authors: Mara
authors: M
authors: Fornaro
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004789:Enzyme Activation / Q000235:genetics; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009133:Muscular Atrophy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D032448:Myoblasts, Skeletal / Q000201:enzymology* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011493:Protein Kinase C; D044365:GTP-Binding Protein alpha Subunits, G12-G13