Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin (Mstn) expression, a negative regulator of muscle growth, is increased by glucocorticoids and Mstn overexpression is associated with lower muscle mass. This suggests that Mstn is required for the catabolic effects of glucocorticoids. We therefore investigated whether Mstn gene disruption could prevent muscle atrophy caused by glucocorticoids. Male knock-out Mstn (KO) and wild-type (WT) mice were subjected to dexamethasone treatment (1 mg/kg.day for 10 days or 5 mg/kg.day for 4 days). In WT mice, daily administration of low dose dexamethasone for 10 days resulted in muscle atrophy (tibialis anterior: ­15%; gastrocnemius: ­13%; p<0.01) due to 15% decrease in the muscle fiber cross-sectional area (CSA) (1621 ± 31 vs 1918 ± 64 mm², p<0.01). In KO mice, there was no reduction of muscle mass nor fiber CSA after dexamethasone treatment. Muscle atrophy after 4 days of high dose dexamethasone was associated with increased expression of enzymes involved in proteolytic pathways: Atrogin-1 (+67%, p<0.05), Murf1: (+89%, p<0.01) and Cathepsin L (+42%, p<0.01). In contrast, the mRNA of these enzymes was 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 (two fold, p<0.01).

In conclusion, our results show that Mstn deletion prevents muscle atrophy in glucocorticoid-treated mice, potentially by down regulating proteolytic pathways, and support the important role of Mstn in muscle atrophy caused by glucocorticoids.