title: Bacterial-excreted small volatile molecule 2-aminoacetophenone induces oxidative stress and apoptosis in murine skeletal muscle.
abstract: Oxidative stress induces mitochondrial dysfunction and facilitates apoptosis, tissue damage or metabolic alterations following infection. We have previously discovered that the Pseudomonas aeruginosa (PA) quorum sensing (QS)-excreted small volatile molecule, 2-aminoacetophenone (2-AA), which is produced in infected human tissue, promotes bacterial phenotypes that favor chronic infection, while also dampening the pathogen‑induced innate immune response, thus compromising muscle function and promoting host tolerance to infection. In this study, murine whole-genome expression data have demonstrated that 2-AA affects the expression of genes involved in reactive oxygen species (ROS) homeostasis, thus producing an oxidative stress signature in skeletal muscle. The results of the present study demonstrated that the expression levels of genes involved in apoptosis signaling pathways were upregulated in the skeletal muscle of 2-AA-treated mice. To confirm the results of our transcriptome analysis, we used a novel high-resolution magic-angle-spinning (HRMAS), proton (1H) nuclear magnetic resonance (NMR) method and observed increased levels of bisallylic methylene fatty acyl protons and vinyl protons, suggesting that 2-AA induces skeletal muscle cell apoptosis. This effect was corroborated by our results demonstrating the downregulation of mitochondrial membrane potential in vivo in response to 2-AA. The findings of the present study indicate that the bacterial infochemical, 2-AA, disrupts mitochondrial functions by inducing oxidative stress and apoptosis signaling and likely promotes skeletal muscle dysfunction, which may favor chronic/persistent infection.
authors.affiliation: Department of Surgery, Microbiology and Immunobiology, Harvard Medical School and Molecular Surgery Laboratory, Center for Surgery, Innovation and Bioengineering, Department of Surgery, Massachusetts General and Shriners Burns Hospitals, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Arunava
authors.initials: A
authors.lastname: Bandyopadhaya
authors.affiliation: Department of Surgery, Microbiology and Immunobiology, Harvard Medical School and Molecular Surgery Laboratory, Center for Surgery, Innovation and Bioengineering, Department of Surgery, Massachusetts General and Shriners Burns Hospitals, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Caterina
authors.initials: C
authors.lastname: Constantinou
authors.affiliation: NMR Surgical Laboratory, Center for Surgery, Innovation and Bioengineering, Department of Surgery, Massachusetts General and Shriners Burns Hospitals, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Psychogios
authors.affiliation: Department of Anesthesiology and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Ueki
authors.affiliation: Department of Anesthesiology and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yasuhara
authors.affiliation: Department of Anesthesiology and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: J A Jeevendra
authors.initials: JA
authors.lastname: Martyn
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Wilhelmy
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mindrinos
authors.affiliation: Department of Surgery, Microbiology and Immunobiology, Harvard Medical School and Molecular Surgery Laboratory, Center for Surgery, Innovation and Bioengineering, Department of Surgery, Massachusetts General and Shriners Burns Hospitals, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
authors.affiliation: NMR Surgical Laboratory, Center for Surgery, Innovation and Bioengineering, Department of Surgery, Massachusetts General and Shriners Burns Hospitals, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: A Aria
authors.initials: AA
authors.lastname: Tzika
mesh_terms: D000098:Acetophenones / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D018384:Oxidative Stress; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000098:Acetophenones; D017382:Reactive Oxygen Species; C055495:2-aminoacetophenone