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Oxidative stress of myosin contributes to skeletal muscle dysfunction in rats with chronic heart failure

¹Institut National de la Santé et de la Recherche Médicale (INSERM) U689, Centre de Recherche Cardiovasculaire INSERM, Hôpital Lariboisière, ²Université Paris 7, Paris; ³Laboratoire d'Anesthésiologie, Département d'Anesthésie-Réanimation, Centre Hospitalier Universitaire (CHU) Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), ⁴Université Paris 6, Paris; ⁵Service d'Accueil des Urgences, CHU Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie, Paris 6, Paris; and ⁶Service d'Explorations Cardio-Respiratoires, Hôpital de Bicêtre, AP-HP, ⁷Université Paris 11, Le Kremlin-Bicêtre, France

Submitted 2 May 2006 ; accepted in final form 7 October 2006

Intrinsic muscle abnormalities affecting skeletal muscle are often reported during chronic heart failure (CHF). Because myosin is the molecular motor of force generation, we sought to determine whether its dysfunction contributes to skeletal muscle weakness in CHF and, if so, to identify the underlying causative factors. Severe CHF was induced in rats by aortic stenosis. In diaphragm and soleus muscles, we investigated in vitro mechanical performance, myosin-based actin filament motility, myosin heavy (MHC) and light (MLC) chain isoform compositions, MLC integrity, caspase-3 activation, and oxidative damage. Diaphragm and soleus muscles from CHF exhibited depressed mechanical performance. Myosin sliding velocities were 16 and 20% slower in CHF than in sham in diaphragm (1.9 ± 0.1 vs. 1.6 ± 0.1 µm/s) and soleus (0.6 ± 0.1 vs. 0.5 ± 0.1 µm/s), respectively (each P < 0.05). The ratio of slow-to-fast myosin isoform did not differ between sham and CHF. Immunoblots with anti-MLC antibodies did not detect the presence of protein fragments, and no activation of caspase-3 was evidenced. Immunolabeling revealed oxidative damage in CHF muscles, and MHC was the main oxidized protein. Lipid peroxidation and expression of oxidized MHC were significantly higher in CHF than in shams. In vitro myosin exposure to increasing ONOO^– concentrations was associated with an increasing amount of oxidized MHC and a reduced myosin velocity. These data provide experimental evidence that intrinsic myosin dysfunction occurs in CHF and may be related to oxidative damage to myosin.

contractile proteins; congestive heart failure; diaphragm

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