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Hypoxia-induced skeletal muscle fiber dysfunction: role for reactive nitrogen species

Department of Pulmonary Diseases and Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Submitted 16 February 2005 ; accepted in final form 16 August 2005

Hypoxia impairs skeletal muscle function, but the precise mechanisms are incompletely understood. In hypoxic rat diaphragm muscle, generation of peroxynitrite is elevated. Peroxynitrite and other reactive nitrogen species have been shown to impair contractility of skinned muscle fibers, reflecting contractile protein dysfunction. We hypothesized that hypoxia induces contractile protein dysfunction and that reactive nitrogen species are involved. In addition, we hypothesized that muscle reoxygenation reverses contractile protein dysfunction. In vitro contractility of rat soleus muscle bundles was studied after 30 min of hyperoxia (PO₂ 90 kPa), hypoxia (PO₂ 5 kPa), hypoxia + 30 µM N^G-monomethyl-L-arginine (L-NMMA, a nitric oxide synthase inhibitor), hyperoxia + 30 µM L-NMMA, and hypoxia (30 min) + reoxygenation (15 min). One part of the muscle bundle was used for single fiber contractile measurements and the other part for nitrotyrosine detection. In skinned single fibers, maximal Ca²⁺-activated specific force (F_max), fraction of strongly attached cross bridges (_fs), rate constant of force redevelopment (k_tr), and myofibrillar Ca²⁺ sensitivity were determined. Thirty minutes of hypoxia reduced muscle bundle contractility. In the hypoxic group, single fiber F_max, _fs, and k_tr were significantly reduced compared with hyperoxic, L-NMMA, and reoxygenation groups. Myofibrillar Ca²⁺ sensitivity was not different between groups. Nitrotyrosine levels were increased in hypoxia compared with all other groups. We concluded that acute hypoxia induces dysfunction of skinned muscle fibers, reflecting contractile protein dysfunction. In addition, our data indicate that reactive nitrogen species play a role in hypoxia-induced contractile protein dysfunction. Reoxygenation of the muscle bundle partially restores bundle contractility but completely reverses contractile protein dysfunction.

nitrotyrosine; denitration; reoxygenation; skinned single fiber; peroxynitrite

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