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J Physiol Volume 586, Number 1, 175-184, January 1, 2008 DOI: 10.1113/jphysiol.2007.147470
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Reactive oxygen species and fatigue-induced prolonged low-frequency force depression in skeletal muscle fibres of rats, mice and SOD2 overexpressing mice

 Joseph D. Bruton1, Nicolas Place1, Takashi Yamada1, José P. Silva2, Francisco H. Andrade3, Anders J. Dahlstedt1, Shi-Jin Zhang1, Abram Katz1, Nils-Göran Larsson4 and Håkan Westerblad1

1 Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden
2 Research Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
3 Department of Physiology, University of Kentucky, Lexington, KY 40536-0298, USA
4 Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, S-141 86 Stockholm, Sweden

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 [Ca2+] ([Ca2+]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 [Ca2+]i in wild-type mouse fibres, whereas rat fibres and mouse SOD2 overexpressing fibres instead displayed a decreased myofibrillar Ca2+ sensitivity. The SOD activity was ~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 Ca2+ sensitivity in rat fibres could be partially reversed by application of the reducing agent dithiothreitol, whereas the decrease in tetanic [Ca2+]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 Ca2+ handling appear more resistant to interventions.

(Received 29 October 2007; accepted after revision 9 November 2007; first published online 15 November 2007)
Corresponding author H. Westerblad: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 171 77, Sweden. Email: hakan.westerblad{at}ki.se






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