title: Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease and its relationship with exercise oxidative stress.
abstract: Exercise triggers skeletal muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD). The objective of this research was to study the specific sites of reactive oxygen species (ROS) production in mitochondria isolated from skeletal muscle of patients with COPD and its relationship with local oxidative stress induced by exercise. Vastus lateralis biopsies were obtained in 16 patients with COPD (66 ± 10 yr; FEV(1), 54 ± 12% ref) and in 14 control subjects with normal lung function who required surgery because of lung cancer (65 ± 7 yr; FEV(1), 91 ± 14% ref) at rest and after exercise. In these biopsies we isolated mitochondria and mitochondrial membrane fragments and determined in vitro mitochondrial oxygen consumption (Mit$$\stackrel{.}{\hbox{ V }}$$o(2)) and ROS production before and after inhibition of complex I (rotenone), complex II (stigmatellin), and complex III (antimycin-A). We related the in vitro ROS production during state 3 respiration), which mostly corresponds to the mitochondria respiratory state during exercise, with skeletal muscle oxidative stress after exercise, as measured by thiobarbituric acid reactive substances.State 3 Mit$$\stackrel{.}{\hbox{ V }}$$o(2) was similar in patients with COPD and control subjects (191 ± 27 versus 229 ± 46 nmol/min/mg; P = 0.058), whereas H(2)O(2) production was higher in the former (147 ± 39 versus 51 ± 8 pmol/mg/h; P < 0.001). The addition of complexI, II, and III inhibitors identify complex III as the main site of H(2)O(2) release by mitochondria in patients with COPD and in control subjects. The mitochondrial production of H(2)O(2) in state 3 respiration was related (r = 0.69; P < 0.001) to postexercise muscle thiobarbituric acid reactive substance levels. Our results show that complex III is the main site of the enhanced mitochondrial H(2)O(2) production that occurs in skeletal muscle of patients with COPD, and the latter appears to contribute to muscle oxidative damage.
authors.affiliation: Servicio de Neumología, Hospital General Universitario Gregorio Marañón. c/ Doctor Ezquerdo 46, 28007 Madrid, Spain. lpuente@separ.es
authors.forename: Luis
authors.initials: L
authors.lastname: Puente-Maestu
authors.forename: Alberto
authors.initials: A
authors.lastname: Tejedor
authors.forename: Alberto
authors.initials: A
authors.lastname: Lázaro
authors.forename: Javier
authors.initials: J
authors.lastname: de Miguel
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez-Sala
authors.forename: Federico
authors.initials: F
authors.lastname: González-Aragoneses
authors.forename: Carlos
authors.initials: C
authors.lastname: Simón
authors.forename: Alvar
authors.initials: A
authors.lastname: Agustí
mesh_terms: D016022:Case-Control Studies; D015444:Exercise; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide