title: Reactive oxygen species and fatigue-induced prolonged low-frequency force depression in skeletal muscle fibres of rats, mice and SOD2 overexpressing mice.
abstract: Skeletal muscle often shows a delayed force recovery after fatiguing stimulation, especially at low stimulation frequencies. In this study we focus on the role of reactive oxygen species (ROS) in this fatigue-induced prolonged low-frequency force depression. Intact, single muscle fibres were dissected from flexor digitorum brevis (FDB) muscles of rats and wild-type and superoxide dismutase 2 (SOD2) overexpressing mice. Force and myoplasmic free [Ca(2+)] ([Ca(2+)](i)) were measured. Fibres were stimulated at different frequencies before and 30 min after fatigue induced by repeated tetani. The results show a marked force decrease at low stimulation frequencies 30 min after fatiguing stimulation in all fibres. This decrease was associated with reduced tetanic [Ca(2+)](i) in wild-type mouse fibres, whereas rat fibres and mouse SOD2 overexpressing fibres instead displayed a decreased myofibrillar Ca(2+) sensitivity. The SOD activity was approximately 50% lower in wild-type mouse than in rat FDB muscles. Myoplasmic ROS increased during repeated tetanic stimulation in rat fibres but not in wild-type mouse fibres. The decreased Ca(2+) sensitivity in rat fibres could be partially reversed by application of the reducing agent dithiothreitol, whereas the decrease in tetanic [Ca(2+)](i) in wild-type mouse fibres was not affected by dithiothreitol or the antioxidant N-acetylcysteine. In conclusion, we describe two different causes of fatigue-induced prolonged low-frequency force depression, which correlate to differences in SOD activity and ROS metabolism. These findings may have clinical implications since ROS-mediated impairments in myofibrillar function can be counteracted by reductants and antioxidants, whereas changes in SR Ca(2+) handling appear more resistant to interventions.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. hakan.westerblad@ki.se
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bruton
authors.forename: Nicolas
authors.initials: N
authors.lastname: Place
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: José P
authors.initials: JP
authors.lastname: Silva
authors.forename: Francisco H
authors.initials: FH
authors.lastname: Andrade
authors.forename: Anders J
authors.initials: AJ
authors.lastname: Dahlstedt
authors.forename: Shi-Jin
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018763:Muscle Fatigue / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000111:Acetylcysteine; D000975:Antioxidants; D002118:Calcium; D004229:Dithiothreitol; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2