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.

Muscle-specific MicroRNA1 (miR1) Targets Heat Shock Protein 70 (HSP70) during Dexamethasone-mediated Atrophy*

“…6, A-C). These data are in agreement with previously published results from Gilson et al (16), which demonstrated that deletion of the myostatin gene prevents glucocorticoid-induced muscle atrophy. Interestingly, we noted that inhibition of Mstn during Dex treatment of C2C12 myotubes not only blunted the expression of atrophy-related genes but also miR1, thereby supporting a role for Mstn in regulation of miR1 during Dex-induced atrophy.…”

“…Furthermore, Dex-mediated atrophy results in a dose-dependent increase in Mstn mRNA and protein expression (15) and deletion of the Myostatin gene can prevent Dex-induced muscle wasting (16), suggesting that Dex-mediated muscle atrophy occurs at least in part through the action of Mstn.…”

Glucocorticoids, metabolism and metabolic diseases

“…Notably, expression of atrogin-1 in response to myostatin treatment appeared to be dependent on increased Foxo1 expression and activity [243]. The functional significance of GC-dependent myostatin upregulation was confirmed in myostatin gene deficient mice, which were resistant to Dex-induced muscle atrophy [245].…”

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

“…Administration of high doses of glucocorticoids induces muscle atrophy and is often associated with elevated myostatin levels (38). The myostatin promoter bears several glucocorticoid response elements, and myostatin deletion has been reported to prevent glucocorticoid-induced muscle wasting (39). The ability of BYM338 to protect muscles from glucocorticoid-induced atrophy and weakness was assessed in a mouse model.…”