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Glucocorticoids Do Not Regulate the Expression of Proteolytic Genes in Skeletal Muscle from Cushing’s Syndrome Patients¹

Institut Natíonal de Recherche Agronomique (C.R., D.T., D.A.), Unité d’Etude du Métabolisme Azoté, and Centre de Recherche en Nutrition Humaine de Clermont-Ferrand, 63122 Ceyrat, France; Service d’Endocrinologie et Maladies Métaboliques (I.T., P.T.), and Service d’Urologie (L.G., J.-P.B., B.G.), Centre Hospitalier Universitaire de Clermont-Ferrand, BP 69, 63003 Clermont-Ferrand Cedex, France

Address all correspondence and requests for reprints to: Didier Attaix, Ph.D., INRA de Theix, Unité d’Etude du Métabolisme Azoté, 63122 Ceyrat, France. E-mail: attaix{at}clermont.inra.fr

Abstract

Glucocorticoids signal enhanced proteolysis in various instances of muscle atrophy and increased gene expression of components of the lysosomal, Ca²⁺-dependent, and/or ubiquitin-proteasome proteolytic pathways in both rat skeletal muscle and myotubes. Cushing’s syndrome is characterized by chronic excessive glucocorticoid production, which results in muscle wasting. We report here no change in messenger RNA levels for cathepsin D (a lysosomal proteinase), m-calpain (a Ca²⁺-activated proteinase), ubiquitin, 14-kDa ubiquitin-activating enzyme E2, and 20S proteasome subunits (i.e. critical components of the ubiquitin-proteasome proteolytic process) in skeletal muscle from such patients. Thus, in striking contrast with animal studies, glucocorticoids did not regulate the expression of muscle proteolytic genes in Cushing’s syndrome. In humans, messenger RNA levels, for at least ubiquitin and proteasome subunits, are elevated in acute situations of muscle wasting, such as head trauma or sepsis. Because Cushing’s syndrome is a chronic catabolic condition, we suggest that the lack of regulation of proteolytic genes in such patients may represent an adaptive regulatory mechanism, preventing sustained increased protein breakdown and avoiding rapid muscle wasting.

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