title: Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation.
abstract: 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.
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine, kbernard@uab.edu.
authors: Karen
authors: K
authors: Bernard
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Naomi J
authors: NJ
authors: Logsdon
authors: Departments of Pathology and Center for Free Radicals Biology and Medicine, University of Alabama, Birmingham, Alabama 35294.
authors: Saranya
authors: S
authors: Ravi
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Na
authors: N
authors: Xie
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Benjamin P
authors: BP
authors: Persons
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Sunad
authors: S
authors: Rangarajan
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Jaroslaw W
authors: JW
authors: Zmijewski
authors: Genetics, and.
authors: Kasturi
authors: K
authors: Mitra
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Gang
authors: G
authors: Liu
authors: Departments of Pathology and Center for Free Radicals Biology and Medicine, University of Alabama, Birmingham, Alabama 35294.
authors: Victor M
authors: VM
authors: Darley-Usmar
authors: From the Division of Pulmonary, Allergy and Critical Care Medicine.
authors: Victor J
authors: VJ
authors: Thannickal
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D004579:Electron Transport; D004734:Energy Metabolism; D006019:Glycolysis; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D010101:Oxygen Consumption; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: differentiation; glycolysis; mitochondria; myofibroblast; p38; transforming growth factor β (TGF-β)