Transforming Growth Factor-β1 Induces Transdifferentiation of Myoblasts into Myofibroblasts via Up-Regulation of Sphingosine Kinase-1/S1P3 Axis
Open Access
- 15 March 2010
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 21 (6), 1111-1124
- https://doi.org/10.1091/mbc.e09-09-0812
Abstract
The pleiotropic cytokine transforming growth factor (TGF)-β1 is a key player in the onset of skeletal muscle fibrosis, which hampers tissue repair. However, the molecular mechanisms implicated in TGFβ1-dependent transdifferentiation of myoblasts into myofibroblasts are presently unknown. Here, we show that TGFβ1 up-regulates sphingosine kinase (SK)-1 in C2C12 myoblasts in a Smad-dependent manner, and concomitantly modifies the expression of sphingosine 1-phosphate (S1P) receptors (S1PRs). Notably, pharmacological or short interfering RNA-mediated inhibition of SK1 prevented the induction of fibrotic markers by TGFβ1. Moreover, inhibition of S1P3, which became the highest expressed S1PR after TGFβ1 challenge, strongly attenuated the profibrotic response to TGFβ1. Furthermore, downstream of S1P3, Rho/Rho kinase signaling was found critically implicated in the profibrotic action of TGFβ1. Importantly, we demonstrate that SK/S1P axis, known to play a key role in myogenesis via S1P2, consequently to TGFβ1-dependent S1PR pattern remodeling, becomes responsible for transmitting a profibrotic, antidifferentiating action. This study provides new compelling information on the mechanism by which TGFβ1 gives rise to fibrosis in skeletal muscle, opening new perspectives for its pharmacological treatment. Moreover, it highlights the pleiotropic role of SK/S1P axis in skeletal myoblasts that, depending on the expressed S1PR pattern, seems capable of eliciting multiple, even contrasting biological responses.Keywords
This publication has 49 references indexed in Scilit:
- Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiationCardiovascular Research, 2009
- Stellate Cell Contraction: Role, Regulation, and Potential Therapeutic TargetClinics in Liver Disease, 2008
- Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor- -stimulated collagen production by cardiac fibroblastsCardiovascular Research, 2008
- Sphingosine Kinases and Sphingosine-1-Phosphate Are Critical for Transforming Growth Factor β-Induced Extracellular Signal-Regulated Kinase 1 and 2 Activation and Promotion of Migration and Invasion of Esophageal Cancer CellsMolecular and Cellular Biology, 2008
- TGF‐β signaling: A tale of two responsesJournal of Cellular Biochemistry, 2007
- Immunomodulator FTY720 Induces Myofibroblast Differentiation via the Lysophospholipid Receptor S1P3 and Smad3 SignalingThe American Journal of Pathology, 2007
- Angiotensin II type 1 receptor blockade attenuates TGF-β–induced failure of muscle regeneration in multiple myopathic statesNature Medicine, 2007
- Entry of muscle satellite cells into the cell cycle requires sphingolipid signalingThe Journal of cell biology, 2006
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001