title: Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure.
abstract: Patients with chronic heart failure (CHF) experience exercise intolerance, fatigue and muscle wasting, which negatively influence their survival. We hypothesized that treatment with either the antioxidant N-acetyl cysteine (NAC) or the proteasome inhibitor bortezomib of rats with monocrotaline-induced CHF may restore inspiratory and limb muscle mass, function, and structure through several molecular mechanisms involved in protein breakdown and metabolism in the diaphragm and gastrocnemius. In these muscles of CHF-cachectic rats with and without treatment with NAC or bortezomib (N = 10/group) and non-cachectic controls, proteolysis (tyrosine release, proteasome activities, ubiquitin-proteasome markers), oxidative stress, inflammation, mitochondrial function, myosin, NF-κB transcriptional activity, muscle structural abnormalities, and fiber morphometry were analyzed together with muscle and cardiac functions. In diaphragm and gastrocnemius of CHF-cachectic rats, tyrosine release, proteasome activity, protein ubiquitination, atrogin-1, MURF-1, NF-κB activity, oxidative stress, inflammation, and structural abnormalities were increased, while muscle and cardiac functions, myosin content, slow- and fast-twitch fiber sizes, and mitochondrial activity were decreased. Concomitant treatment of CHF-cachectic rats with NAC or bortezomib improved protein catabolism, oxidative stress, inflammation, muscle fiber sizes, function and damage, superoxide dismutase and myosin levels, mitochondrial function (complex I, gastrocnemius), cardiac function and decreased NF-κB transcriptional activity in both muscles. Treatment of CHF-cachectic animals with NAC or bortezomib attenuated the functional (heart, muscles), biological, and structural alterations in muscles. Nonetheless, future studies conducted in actual clinical settings are warranted in order to assess the potential beneficial effects and safety concerns of these pharmacological agents on muscle mass loss and wasting in CHF-cachectic patients.
authors.affiliation: Department of Pulmonology-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Barreiro
authors.affiliation: Department of Pulmonology-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Puig-Vilanova
authors.affiliation: Department of Pulmonology-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Marin-Corral
authors.affiliation: Department of Pulmonology-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Chacón-Cabrera
authors.affiliation: Department of Pulmonology-Muscle and Respiratory System Research Unit (URMAR), IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), Barcelona, Spain.|Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Salazar-Degracia
authors.affiliation: Servicio de Neumología, Hospital General Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mateu
authors.affiliation: Servicio de Neumología, Hospital General Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Puente-Maestu
authors.affiliation: Unitat de Patologia Neuromuscular i Mitocondrial, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Arumí
authors.affiliation: Unitat de Patologia Neuromuscular i Mitocondrial, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.affiliation: Department of Cardiology, Hospital del Mar, Heart Diseases Biomedical Research Group, IMIM, and Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Molina
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D000069286:Bortezomib / Q000008:administration & dosage*; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016686:Monocrotaline / Q000633:toxicity; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D059748:Proteolysis / Q000187:drug effects; D051381:Rats
chemical_list: D016328:NF-kappa B; D000069286:Bortezomib; D016686:Monocrotaline; D000111:Acetylcysteine