A murine model of glucocorticoid myopathy alleviation using androgen therapy
Sandor, Nicolae Lucian
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Glucocorticoids (GC) are used widely for the treatment of a large number of inflammatory conditions. A loss in muscle mass and increases in muscle weakness are common complications of GC therapy. Androgen therapy has been suggested to reverse GC-associated muscle loss (GAML), but evidence of its effectiveness is inconsistent. Herein, I established a mouse model of GAML. Young adult male mice receiving 10 mg/(kg day) of the GC dexamethasone (Dexa) s.c. daily, for a week, lost 3% of their total body weight. Based on NMR lean body mass quantification and muscle dissection, more than 10% of their muscle mass was lost. More than half of the Dexa-induced muscle loss could be reversed by co-administration of 35 mg/(kg day) of testosterone (Testo). To my knowledge, this is the first mouse model of GAML demonstrating alleviation by Testo. Dexa-upregulated intramuscular atrogene expression and proteasome catalytic activity were suppressed by Testo co-administration. Dexa downregulated cathepsin L enzymatic activity and beclin expression, indicating that lysosome was not a major effector of GAML. Changes in calpain 1 and in translation factors 4E-BP, eIF3f and eIF2, following Testo treatment, were inconclusive. The changes in proteasome activity and atrogene expression were correlated with changes in expression of Foxo 1, 3a, and 4. Pro-catabolic factors REDD1 and Klf15 were repressed by Testo co-administration. C2C12 differentiated myotubes were used to model GAML in vitro. Myotube diameter and total protein were reduced by Dexa, and restored by Testo co-administration. Changes in C2C12 total protein were correlated with changes in protein degradation. Dexa-induced proteolysis was inhibited by the proteasome inhibitor MG132. In vivo, Dexa reduced intramuscular IGF-I expression, an effect reversed by Testo co-administration. In C2C12, inhibition of IGF-1R signaling with picropodophyllin did not modify Testo protective effect. Mechanisms potentially explaining these observations are discussed. In summary, my model demonstrates that Testo protective effect in GAML is mainly anti-catabolic, through the reversal of proteasome upregulation induced by Dexa. In vivo, Testo stimulates a potentially protective intramuscular IGF-I response. The roles of protein synthesis and IGF-I in anabolic myoprotection could not be addressed in these models, and require further investigations.