title: Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.
abstract: Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H₂O₂production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100μM) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon.
authors.affiliation: University of Strasbourg, Faculty of Medicine, Fédération de Médecine Translationelle, EA 3072, 11 rue Humann, Strasbourg, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, 67091 Strasbourg, France.; Department of Clinical Pharmacology & Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Singh
authors.affiliation: University of Strasbourg, Faculty of Medicine, Fédération de Médecine Translationelle, EA 3072, 11 rue Humann, Strasbourg, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Charles
authors.affiliation: University of Strasbourg, Faculty of Medicine, Fédération de Médecine Translationelle, EA 3072, 11 rue Humann, Strasbourg, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, 67091 Strasbourg, France.
authors.forename: Anna-Isabel
authors.initials: AI
authors.lastname: Schlagowski
authors.affiliation: Department of Clinical Pharmacology & Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.affiliation: Department of Clinical Pharmacology & Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bonifacio
authors.affiliation: University of Strasbourg, Faculty of Medicine, Fédération de Médecine Translationelle, EA 3072, 11 rue Humann, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Piquard
authors.affiliation: Department of Clinical Pharmacology & Toxicology, Department of Biomedicine, University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.affiliation: University of Strasbourg, Faculty of Medicine, Fédération de Médecine Translationelle, EA 3072, 11 rue Humann, Strasbourg, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, 67091 Strasbourg, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.affiliation: University of Strasbourg, Faculty of Medicine, Fédération de Médecine Translationelle, EA 3072, 11 rue Humann, Strasbourg, France; CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, B.P. 426, 67091 Strasbourg, France.. Electronic address: zolljoffrey@yahoo.com.
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D059165:Hormesis / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063269:Mitochondrial Turnover / Q000187:drug effects; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020011:Protective Agents; D017382:Reactive Oxygen Species; D000111:Acetylcysteine
keywords: Apoptosis; Mitohormesis; Myoblast; N-acetylcysteine; Reductive stress; Statin