title: Antioxidant treatments do not improve force recovery after fatiguing stimulation of mouse skeletal muscle fibres.
abstract: The contractile performance of skeletal muscle declines during intense activities, i.e. fatigue develops. Fatigued muscle can enter a state of prolonged low-frequency force depression (PLFFD). PLFFD can be due to decreased tetanic free cytosolic [Ca(2+) ] ([Ca(2+) ]i ) and/or decreased myofibrillar Ca(2+) sensitivity. Increases in reactive oxygen and nitrogen species (ROS/RNS) may contribute to fatigue-induced force reductions. We studied whether pharmacological ROS/RNS inhibition delays fatigue and/or counteracts the development of PLFFD. Mechanically isolated mouse fast-twitch fibres were fatigued by sixty 150 ms, 70 Hz tetani given every 1 s. Experiments were performed in standard Tyrode solution (control) or in the presence of: NADPH oxidase (NOX) 2 inhibitor (gp91ds-tat); NOX4 inhibitor (GKT137831); mitochondria-targeted antioxidant (SS-31); nitric oxide synthase (NOS) inhibitor (l-NAME); the general antioxidant N-acetylcysteine (NAC); a cocktail of SS-31, l-NAME and NAC. Spatially and temporally averaged [Ca(2+) ]i and peak force were reduced by ∼20% and ∼70% at the end of fatiguing stimulation, respectively, with no marked differences between groups. PLFFD was similar in all groups, with 30 Hz force being decreased by ∼60% at 30 min of recovery. PLFFD was mostly due to decreased tetanic [Ca(2+) ]i in control fibres and in the presence of NOX2 or NOX4 inhibitors. Conversely, in fibres exposed to SS-31 or the anti ROS/RNS cocktail, tetanic [Ca(2+) ]i was not decreased during recovery so PLFFD was only caused by decreased myofibrillar Ca(2+) sensitivity. The cocktail also increased resting [Ca(2+) ]i and ultimately caused cell death. In conclusion, ROS/RNS-neutralizing compounds did not counteract the force decline during or after induction of fatigue.
authors: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors: Arthur J
authors: AJ
authors: Cheng
authors: Joseph D
authors: JD
authors: Bruton
authors: Johanna T
authors: JT
authors: Lanner
authors: Håkan
authors: H
authors: Westerblad
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018763:Muscle Fatigue; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D002118:Calcium
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