title: Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol.
abstract: Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta(1)-beta(2)-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a beta(1) selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective beta-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance.
authors.affiliation: CNR Institute of Neurosciences, Unit for Neuromuscular Biology and Pathophysiology, Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35100 Padova, Italy. ldl@bio.unipd.it
authors.forename: Luciano
authors.initials: L
authors.lastname: Dalla Libera
authors.forename: Barbara
authors.initials: B
authors.lastname: Ravara
authors.forename: Valerio
authors.initials: V
authors.lastname: Gobbo
authors.forename: Daniela
authors.initials: D
authors.lastname: Danieli Betto
authors.forename: Elena
authors.initials: E
authors.lastname: Germinario
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Vescovo
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017298:Bisoprolol / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009210:Myofibrils; D010084:Oxidation-Reduction; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D009124:Muscle Proteins; D011412:Propanolamines; D000077261:Carvedilol; D016686:Monocrotaline; D017298:Bisoprolol