Effects of corticosterone on muscle mitochondria identifying different sensitivity to glucocorticoids in Lewis and Fischer rats

Abstract

Duclos, Martine, Caroline Gouarne, Cyril Martin, Christophe Rocher, Pierre Mormède, and Thierry Letellier. Effects of corticosterone on muscle mitochondria identifying different sensitivity to glucocorticoids in Lewis and Fischer rats. Am J Physiol Endocrinol Metab 286: E159-E167, 2004. First published September 9, 2003 10.1152/ajpendo.00281.2003.-Previous studies in rat have demonstrated decreased number of mitochondria and uncoupling of oxidative phosphorylation after administration of glucocorticoids but at supraphysiological doses and using synthetic glucocorticoids. To analyze the relationships between corticosterone levels (the natural glucocorticoid in rat) and muscle mitochondrial metabolism, Lewis and Fischer 344 rats were bilaterally adrenalectomized and implanted with different corticosterone pellets (0, 12, 50, 100, and 200 mg of corticosterone). Rats bearing a corticosterone pellet delivering corticosterone at concentrations in the range of chronic stress-induced levels presented a lower amount of functional muscle mitochondria with a decrease in cytochrome c oxidase and citrate synthase activities and a depletion of mitochondrial DNA. Moreover, a strain difference in tissue sensitivity to corticosterone was depicted both in end-organ sensitive to glucocorticoids (body, thymus, and adrenal weights) and in muscle mitochondrial metabolism (Lewis Ͼ Fischer). Interestingly, this strain difference was also observed in the absence of corticosterone, with a deleterious effect on muscle mitochondrial metabolism in Fischer rats, whereas no effects were observed in Lewis rats. We therefore postulate that corticosterone is necessary for muscle mitochondrial metabolism exerting its effects in Fischer rats with an inverted U curve, whereby too little (only Fischer) or too much (Fischer and Lewis) corticosterone is deleterious to muscle mitochondrial metabolism. In conclusion, we propose a general model of coordinate regulation of mitochondrial energetic metabolism by glucocorticoids. skeletal muscle; cytochrome c oxidase; tissue sensitivity to glucocorticoids GLUCOCORTICOIDS (GC), hormones released by the adrenal cortex, have numerous homeostatic and stress-response functions. A delicate balance exists between the protective effects of adrenal steroids secreted in response to stressful experiences and the negative consequences that GC may have for many processes (20). For example, in skeletal muscles, GC insufficiency leads to debilitating fatigue, myalgia, and general muscle weakness (27), whereas excess GC causes muscular atrophy and a decreased rate of muscle protein synthesis (2). Among several mechanisms leading to muscle wasting in GC-induced myopathy, defects in mitochondrial function appear to be involved (21,22,35). With the administration of supraphysiological doses of GC in rat, electron microscopic and biochemical studies have demonstrated enlarged mitochondrial volume, decreased number of mitochondria, decreased substrate utilization, and uncoupling of oxidative phosphorylation (21). Studies of the...

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