GLUCOCORTICOID LONG-TERM TREATMENT INDUCES OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND ATROPHY OF SKELETAL MUSCLES

Abstract

The mechanism of glucocorticoid-induced atrophy remains unclear. Objectives: to evaluate the involvement of oxidative stress, connexin hemichannels (Cx HCs) and mitochondrial dysfunction in dexamethasone (DEX)-induced muscle atrophy. Methods: We used muscle specific Cx43/Cx45 expression deficient and wild-type mice treated with DEX or DEX+vitaminE. Atrophy was evaluated by atrogin-1 reactivity (immunofluorescense) and cross sectional area (CSA) of myofibers. The functional state of mitochondria was evaluated by measuring oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and mitochondrial superoxide production (mtROS). The Cx expression was evaluated by immunofluorescence. Results: At day 7th of DEX treatment myofibers of wild-type mice showed reduced MMP, increased mtROS, reduced OCR, increased atrogin-1 and reduced CSA.These changes were absent in muscles of wild-type mice treated with DEX + vitaminE and in muscles Cx43/45 expression deficient mice.Moreover, DEX induced de novo expression of Cx43/Cx45 in myofibers of wild-type mice, which was prevented by vitaminE. Conclusions: DEX induces oxidative stress and Cx43/Cx45 de novo expression, which have a negative impact on mitochondrial function leading to muscle atrophy. Consequently, these side effects of chronic glucocorticoid treatment might be avoided by co-administration of antioxidant agents such as vitaminE and a Cx HC blocker.