Idiopathic Fatigue of Aging Oxidative Stress and Fatigue

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Idiopathic Fatigue of Aging Oxidative Stress and Fatigue Francisco H. Andrade Department of Physiology

Idiopathic Fatigue of Aging Oxidative Stress and Fatigue Francisco H. Andrade Department of Physiology University of Kentucky, Lexington KY 40536 USA

CNN: “How Olympic Athletes Get Their Fuel” “Dinner for the long-distance runner would be

CNN: “How Olympic Athletes Get Their Fuel” “Dinner for the long-distance runner would be carbs -- potatoes, rice, bread -- with some protein -- salmon, chicken, lean beef -- and vegetables mixed in, she said. Antioxidants are key because athletes produce a lot of free radicals, which can result in cell damage. ” (Quote attributed to Tara Gidus, dietician for the Orlando Magic) http: //www. cnn. com/2008/HEALTH/diet. fitness/08/14/olympic. diet/index. html

Oxidative stress and fatigue • Free radicals and skeletal muscle, a historical link (of

Oxidative stress and fatigue • Free radicals and skeletal muscle, a historical link (of sorts) – Gerschmann, et al. Science 119: 623, 1954 – Fenn, et al. PNAS 43: 1027, 1957 • Oxidative stress after exhaustive exercise – Dillard, et al. J. Appl. Physiol. 45: 927, 1978 • Free radicals and muscle damage after exercise – Davies, et al. Biochem. Biophys. Res. Commun. 107: 1198, 1982 • Antioxidant depletion accelerates fatigue – Morales, et al. Am. J. Respir. Crit. Care Med. 149: 915, 1994 • Exogenous antioxidants delay fatigue – Shindoh, et al. J. Appl. Physiol. 68: 2107, 1990

Reactive oxygen species: Cellular sources • Mitochondrial respiration – Duchen. J. Physiol. 516: 1,

Reactive oxygen species: Cellular sources • Mitochondrial respiration – Duchen. J. Physiol. 516: 1, 1999 • Non-mitochondrial oxidoreductases – Kobzik, et al. Nature 372: 546, 1994 • Xanthine dehydrogenase/oxidase – Apple, et al. Am. J. Anat. 192: 319, 1991 • Eicosanoid metabolism – Morrow and Roberts. Prog. Lipid Res. 36: 1, 1997

Reactive oxygen species: Cellular sources Cellular heterogeneity Rat Diaphragm: DCF fluorescence

Reactive oxygen species: Cellular sources Cellular heterogeneity Rat Diaphragm: DCF fluorescence

Reactive oxygen species: Cellular targets • Sarcoplasmic reticulum – Aghdasi, et al. J. Biol.

Reactive oxygen species: Cellular targets • Sarcoplasmic reticulum – Aghdasi, et al. J. Biol. Chem. 272: 3739, 1997 • Myofilaments – Crowder and Cooke. J. Muscle Res. Cell. Motil. 5: 131, 1984 • Metabolic enzymes – Ziegler. Annu. Rev. Biochem. 54: 305, 1985 • Signal transduction – Li, et al. Am. J. Physiol. Cell Physiol. 285: C 806, 2003

Reactive oxygen species: Effects on the sarcoplasmic reticulum Andrade, et al. , FASEB J

Reactive oxygen species: Effects on the sarcoplasmic reticulum Andrade, et al. , FASEB J 10. 1096/fj. 00 -0507 fje

Reactive oxygen species: Effects on myofilament function Andrade, et al. J Physiol 509: 565,

Reactive oxygen species: Effects on myofilament function Andrade, et al. J Physiol 509: 565, 1998

Reactive oxygen species: Muscle function and dysfunction Andrade, et al. FASEB J 15: 309,

Reactive oxygen species: Muscle function and dysfunction Andrade, et al. FASEB J 15: 309, 2001

Skeletal muscle: Not just for walking

Skeletal muscle: Not just for walking

Outstanding issues: • Sources of reactive oxygen species – During activity vs. disease –

Outstanding issues: • Sources of reactive oxygen species – During activity vs. disease – Effects of age – Species and cellular targets • Cellular and tissue heterogeneity – Production and sensitivity – Fiber type differences – Motor group differences • Interventions – Exogenous vs. endogenous antioxidants – Functional vs. biochemical endpoints – Worry about “tonic” levels of reactive oxygen species?