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Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease
Author(s) -
Wei Lan,
Salahura Gheorghe,
Boncompagni Simona,
Kasischke Karl A.,
Protasi Feliciano,
Sheu SheyShing,
Dirksen Robert T.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-187252
Subject(s) - superoxide , skeletal muscle , mitochondrion , hypermetabolism , tetanic stimulation , chemistry , oxidative phosphorylation , oxidative stress , malignant hyperthermia , biology , biochemistry , microbiology and biotechnology , biophysics , endocrinology , medicine , pathology , neurotransmission , receptor , enzyme
Mitochondrial superoxide flashes (mSOFs) are stochastic events of quantal mitochondrial superoxide generation. Here, we used flexor digitorum brevis muscle fibers from transgenic mice with muscle‐specific expression of a novel mitochondrial‐targeted superoxide biosensor (mt‐cpYFP) to characterize mSOF activity in skeletal muscle at rest, following intense activity, and under pathological conditions. Results demonstrate that mSOF activity in muscle depended on electron transport chain and adenine nucleotide translocase functionality, but it was independent of cyclophilin‐D‐mediated mitochondrial permeability transition pore activity. The diverse spatial dimensions of individual mSOF events were found to reflect a complex underlying morphology of the mitochondrial network, as examined by electron microscopy. Muscle activity regulated mSOF activity in a biphasic manner. Specifically, mSOF frequency was significantly increased following brief tetanic stimulation (18.1 ± 1.6 to 22.3±2.0 flashes/1000 μm 2 ·100 s before and after 5 tetani) and markedly decreased (to 7.7±1.6 flashes/1000 μm 2 ·100 s) following prolonged tetanic stimulation (40 tetani). A significant temperature‐dependent increase in mSOF frequency (11.9±0.8 and 19.8±2.6 flashes/1000 μm 2 ·100 s at 23°C and 37°C) was observed in fibers from RYR1 Y522S/WT mice, a mouse model of malignant hyperthermia and heat‐induced hypermetabolism. Together, these results demonstrate that mSOF activity is a highly sensitive biomarker of mitochondrial respiration and the cellular metabolic state of muscle during physiological activity and pathological oxidative stress.—Wei, L., Salahura, G., Boncompagni, S., Kasischke, K. A., Protasi, F., Sheu, S.‐S., Dirksen, R. T. Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease. FASEB J. 25, 3068–3078 (2011). www.fasebj.org