Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation

• Published in: The Journal of biological chemistry Vol. 290; no. 42; pp. 25427 - 25438
• Main Authors: Bernard, Karen, Logsdon, Naomi J., Ravi, Saranya, Xie, Na, Persons, Benjamin P., Rangarajan, Sunad, Zmijewski, Jaroslaw W., Mitra, Kasturi, Liu, Gang, Darley-Usmar, Victor M., Thannickal, Victor J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.10.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Cell Differentiation; Cell Line; differentiation; Electron Transport; Energy Metabolism; Glycolysis; Humans; Lung - cytology; Lung - metabolism; Metabolism; mitochondria; Mitochondria - metabolism; myofibroblast; Myofibroblasts - cytology; Myofibroblasts - metabolism; Oxygen Consumption; p38; p38 Mitogen-Activated Protein Kinases - metabolism; Transforming Growth Factor beta1 - physiology; transforming growth factor β (TGF-β); differentiation; p38; myofibroblast; mitochondria; glycolysis; transforming growth factor β (TGF-β)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.646984

Contraction is crucial in maintaining the differentiated phenotype of myofibroblasts. Contraction is an energy-dependent mechanism that relies on the production of ATP by mitochondria and/or glycolysis. Although the role of mitochondrial biogenesis in the adaptive responses of skeletal muscle to exercise is well appreciated, mechanisms governing energetic adaptation of myofibroblasts are not well understood. Our study demonstrates induction of mitochondrial biogenesis and aerobic glycolysis in response to the differentiation-inducing factor transforming growth factor β1 (TGF-β1). This metabolic reprogramming is linked to the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Inhibition of p38 MAPK decreased accumulation of active peroxisome proliferator-activated receptor γ coactivator 1α in the nucleus and altered the translocation of mitochondrial transcription factor A to the mitochondria. Genetic or pharmacologic approaches that block mitochondrial biogenesis or glycolysis resulted in decreased contraction and reduced expression of TGF-β1-induced α-smooth muscle actin and collagen α-2(I) but not of fibronectin or collagen α-1(I). These data indicate a critical role for TGF-β1-induced metabolic reprogramming in regulating myofibroblast-specific contractile signaling and support the concept of integrating bioenergetics with cellular differentiation. Background: Myofibroblasts, by virtue of their functions, are highly energy-dependent. Results: TGF-β1-induced myofibroblast differentiation is associated with a metabolic reprogramming. This metabolic adaptation is essential to the expression of myofibroblast-related genes. Conclusion: Metabolic reprogramming is a hallmark of myofibroblast differentiation and is critical for its contractile function. Significance: This is the first report that links bioenergetics to myofibroblast activation.