title: Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy.
abstract: Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin expression, a negative regulator of muscle growth, is increased by glucocorticoids and myostatin overexpression is associated with lower muscle mass. This suggests that myostatin is required for the catabolic effects of glucocorticoids. We therefore investigated whether myostatin gene disruption could prevent muscle atrophy caused by glucocorticoids. Male myostatin knockout (KO) and wild-type mice were subjected to dexamethasone treatment (1 mg/kg.d for 10 d or 5 mg/kg.d for 4 d). In wild-type mice, daily administration of low-dose dexamethasone for 10 d resulted in muscle atrophy (tibialis anterior: -15%; gastrocnemius: -13%; P < 0.01) due to 15% decrease in the muscle fiber cross-sectional area (1621 +/- 31 vs. 1918 +/- 64 microm(2), P < 0.01). In KO mice, there was no reduction of muscle mass nor fiber cross-sectional area after dexamethasone treatment. Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity. In contrast, the mRNA of these enzymes and the proteasomal activity were not significantly affected by dexamethasone in KO mice. Muscle IGF-I mRNA was paradoxically decreased in KO mice (-35%, P < 0.05); this was associated with a potentially compensatory increase of IGF-II expression in both saline and dexamethasone-treated KO mice (2-fold, P < 0.01). In conclusion, our results show that myostatin deletion prevents muscle atrophy in glucocorticoid-treated mice, by blunting the glucocorticoid-induced enhanced proteolysis, and suggest an important role of myostatin in muscle atrophy caused by glucocorticoids.
authors.affiliation: Unité de Diabétologie et Nutrition, Université Catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Gilson
authors.forename: O
authors.initials: O
authors.lastname: Schakman
authors.forename: L
authors.initials: L
authors.lastname: Combaret
authors.forename: P
authors.initials: P
authors.lastname: Lause
authors.forename: L
authors.initials: L
authors.lastname: Grobet
authors.forename: D
authors.initials: D
authors.lastname: Attaix
authors.forename: J M
authors.initials: JM
authors.lastname: Ketelslegers
authors.forename: J P
authors.initials: JP
authors.lastname: Thissen
mesh_terms: D000818:Animals; D001835:Body Weight; D003907:Dexamethasone / Q000494:pharmacology*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009210:Myofibrils / Q000201:enzymology / Q000473:pathology; D055435:Myostatin; D009929:Organ Size; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; C525912:Mstn protein, mouse; D055435:Myostatin; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex