Dexamethasone (DEX) is used as anti-inflammatory and immunosuppressant drug. DEX treatment side-effects are several including muscle weakness, hypertension and microvascular rarefaction, which is attributed to an imbalance in angiogenesis and apoptotic signaling. DEX alters mitochondrial function in muscle cells but nothing is known of DEX effects in endothelial cells that could explain induced rarefaction. Physical training improves mitochondrial function and biogenesis by increasing Sirtuin 1 (Sirt-1) activity and nicotinamide adenine dinucleotide (NAD+) production. We have shown that physical training ameliorates vascular dysfunction and inhibits rarefaction in DEX treatments by mechanisms not fully understood. Thus, the overall goal of this project is to investigate if exercise training prevents DEX-induced vascular rarefaction by improving mitochondrial function. We will establish the effects of DEX in metabolic biomarkers using sedentary and trained muscles and interrogate specific changes in mitochondrial function in cells. Specifically, we will (1) establish the effects of DEX on NAD+, redox changes and cell apoptosis ; (2) establish the effects of DEX on bioenergetics using extra cellular flux bioenergetics analysis. The changes in mitochondrial biogenesis and mitophagy will be performed by confocal fluorescence, qPCR, and western blots; and (3) verify whether mitochondrial-targeted antioxidants (mito-Q and mitoCP) improve mitochondrial and cellular bioenergetics in DEX-treatment. As a result of this project, we will better understand the biochemical mechanisms involved in DEX-induced rarefaction and conceivably identify additional measures to control its vascular effects.
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