title: Pigment epithelium-derived factor stimulates skeletal muscle glycolytic activity through NADPH oxidase-dependent reactive oxygen species production.
abstract: Pigment epithelium-derived factor is a multifunctional serpin implicated in insulin resistance in metabolic disorders. Recent evidence suggests that exposure of peripheral tissues such as skeletal muscle to PEDF has profound metabolic consequences with predisposition towards chronic conditions such as obesity, type 2 diabetes, metabolic syndrome and polycystic ovarian syndrome. Chronic inflammation shifts muscle metabolism towards increased glycolysis and decreased oxidative metabolism. In the present study, we demonstrate a novel effect of PEDF on cellular metabolism in mouse cell line (C2C12) and human primary skeletal muscle cells. PEDF addition to skeletal muscle cells induced enhanced phospholipase A2 activity. This was accompanied with increased production of reactive oxygen species in a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent manner that triggered a shift towards a more glycolytic phenotype. Extracellular flux analysis and glucose consumption assays demonstrated that PEDF treatment resulted in enhanced glycolysis but did not change mitochondrial respiration. Our results demonstrate that skeletal muscle cells express a PEDF-inducible oxidant generating system that enhances glycolysis but is sensitive to antioxidants and NADPH oxidase inhibition.
authors.affiliation: Curtin Health Innovation Research Institute, Bentley 6102, Australia; School of Pharmacy, Curtin University, Bentley 6102, Australia; Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin University, Bentley 6102, Australia; School of Biomedical Sciences, Curtin University, Bentley 6102, Australia.
authors.forename: Revathy
authors.initials: R
authors.lastname: Carnagarin
authors.affiliation: Curtin Health Innovation Research Institute, Bentley 6102, Australia; School of Biomedical Sciences, Curtin University, Bentley 6102, Australia.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Carlessi
authors.affiliation: Curtin Health Innovation Research Institute, Bentley 6102, Australia; School of Biomedical Sciences, Curtin University, Bentley 6102, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
authors.affiliation: Curtin Health Innovation Research Institute, Bentley 6102, Australia; Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin University, Bentley 6102, Australia.
authors.forename: Arun M
authors.initials: AM
authors.lastname: Dharmarajan
authors.affiliation: Curtin Health Innovation Research Institute, Bentley 6102, Australia; School of Pharmacy, Curtin University, Bentley 6102, Australia. Electronic address: Crispin.Dass@curtin.edu.au.
authors.forename: Crispin R
authors.initials: CR
authors.lastname: Dass
mesh_terms: D000818:Animals; D005136:Eye Proteins / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015843:Serpins / Q000494:pharmacology*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D019255:NADPH Oxidases; D009414:Nerve Growth Factors; D017382:Reactive Oxygen Species; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: Antioxidants; Glycolysis; NADPH oxidase; PEDF; Reactive oxygen species; Skeletal muscle