title: Pharmacological targeting of mitochondrial reactive oxygen species counteracts diaphragm weakness in chronic heart failure.
abstract: Diaphragm muscle weakness in chronic heart failure (CHF) is caused by elevated oxidants and exacerbates breathing abnormalities, exercise intolerance, and dyspnea. However, the specific source of oxidants that cause diaphragm weakness is unknown. We examined whether mitochondrial reactive oxygen species (ROS) cause diaphragm weakness in CHF by testing the hypothesis that CHF animals treated with a mitochondria-targeted antioxidant have normal diaphragm function. Rats underwent CHF or sham surgery. Eight weeks after surgeries, we administered a mitochondrial-targeted antioxidant (MitoTEMPO; 1 mg·kg(-1)·day(-1)) or sterile saline (Vehicle). Left ventricular dysfunction (echocardiography) pre- and posttreatment and morphological abnormalities were consistent with the presence of CHF. CHF elicited a threefold (P < 0.05) increase in diaphragm mitochondrial H2O2 emission, decreased diaphragm glutathione content by 23%, and also depressed twitch and maximal tetanic force by ∼20% in Vehicle-treated animals compared with Sham (P < 0.05 for all comparisons). Diaphragm mitochondrial H2O2 emission, glutathione content, and twitch and maximal tetanic force were normal in CHF animals receiving MitoTEMPO. Neither CHF nor MitoTEMPO altered the diaphragm protein levels of antioxidant enzymes: superoxide dismutases (CuZn-SOD or MnSOD), glutathione peroxidase, and catalase. In both Vehicle and MitoTEMPO groups, CHF elicited a ∼30% increase in cytochrome c oxidase activity, whereas there were no changes in citrate synthase activity. Our data suggest that elevated mitochondrial H2O2 emission causes diaphragm weakness in CHF. Moreover, changes in protein levels of antioxidant enzymes or mitochondrial content do not seem to mediate the increase in mitochondria H2O2 emission in CHF and protective effects of MitoTEMPO.
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Orlando
authors: O
authors: Laitano
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Bumsoo
authors: B
authors: Ahn
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Nikhil
authors: N
authors: Patel
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Philip D
authors: PD
authors: Coblentz
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Ashley J
authors: AJ
authors: Smuder
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Jeung-Ki
authors: JK
authors: Yoo
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Demetra D
authors: DD
authors: Christou
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida.
authors: Peter J
authors: PJ
authors: Adhihetty
authors: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida ferreira@hhp.ufl.edu.
authors: Leonardo F
authors: LF
authors: Ferreira
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018908:Muscle Weakness / Q000378:metabolism / Q000503:physiopathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D013481:Superoxides; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D003576:Electron Transport Complex IV; D005978:Glutathione
keywords: force; inspiratory muscle; mycardial infarction; oxidants; skeletal muscle