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1B and C). Thus, we observed no signs of impaired contractile function or Ca2+ handling in the unfatigued state in muscles from young mtDNA mutator mice. Fatigue induced by repeated tetanic stimulation was studied in fast-twitch FDB fibres of young mtDNA mutator and Control mice. Typical records and mean data from these fatigue experiments are shown in Fig. 2. The two groups showed the same pattern during the first ten tetani, i.e. tetanic [Ca2+]i increased by ?20% while tetanic force decreased by ?15%. Thereafter the two groups diverged and both tetanic [Ca2+]i and force decreased more rapidly in the mtDNA mutator fibres. At the end of the series of 50 fatiguing contractions, fibres of young mtDNA mutator mice displayed ?25% lower tetanic [Ca2+]i (P http://www.selleckchem.com/products/i-bet-762.html stimulation (Westerblad & Allen, 1991; Allen et al. 2008). Basal [Ca2+]i was similar (?100 nm) in the two groups before fatiguing stimulation, while in the fatigued state it was markedly higher in http://www.selleck.cn/products/lee011.html mtDNA mutator (257 �� 38 nm) than in Control (167 �� 12 nm) fibres (P http://www.selleckchem.com/products/epacadostat-incb024360.html studied in isolated whole EDL muscles. Oxygen diffusion is restricted in isolated whole muscles and deeper parts of the muscle are likely to become hypoxic during repeated stimulation (Barclay, 2005), which means that differences in mitochondrial respiration may have limited impact on fatigue development. Accordingly, the force decrease during fatiguing stimulation was similar in isolated mtDNA mutator and Control EDL muscles; at the end of the 50 fatiguing tetani, force was decreased to 24.6 �� 2.3 and 22.9 �� 1.2% of the original in mtDNA mutator and Control muscles, respectively (n= 12 in both groups). Defective mitochondrial function might be associated with increased ROS production and we therefore measured mitochondrial O2��? with MitoSOX Red. Neither young mtDNA mutator nor Control fibres showed any increase in MitoSOX fluorescence during 50 fatiguing tetani (Fig. 4A).