Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells.
Skeletal myopathy is a common complication of endogenous and exogenous glucocorticoid excess, yet its pathogenetic mechanisms remain unclear. There is accumulating evidence that mitochondrial dysfunction and oxidative stress are involved in this process. To explore the glucocorticoid-induced transcriptional adaptations that may affect mitochondrial function in skeletal muscle, we studied gene expression profiles in dexamethasone-treated primary human skeletal myocytes using a cDNA microarray, which contains 501 mitochondria-related genes. We found that monoamine oxidase A (MAO-A) was the most significantly up-regulated gene. MAO-A is the primary enzyme metabolizing catecholamines and dietary amines, and its role in skeletal muscle remains largely unexplored. Dexamethasone induced dose- and time-dependent increases of MAO-A gene and protein expression, while its effects on MAO-B were minimal. Both the glucocorticoid receptor (GR) and the Sp1 transcription factor were required for dexamethasone-induced MAO-A mRNA expression, as blockade of the GR with RU 486 or ablation of Sp1 binding with mithramycin abrogated MAO-A mRNA induction. The observed dexamethasone effect was biologically functional, as this steroid significantly increased MAO-mediated hydrogen peroxide production. We suggest that MAO-A-mediated oxidative stress can lead to cell damage, representing a novel pathogenetic mechanism for glucocorticoid-induced myopathy and a potential target for therapeutic intervention.
Manoli
Irini
I
Endocrine Section, Laboratory of Clinical Investigation, NCCAM, NIH, Bethesda, Maryland 20892, USA. manolii@mail.nih.gov
Le
Hanh
H
Alesci
Salvatore
S
McFann
Kimberly K
KK
Su
Yan A
YA
Kino
Tomoshige
T
Chrousos
George P
GP
Blackman
Marc R
MR
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D003907:Dexamethasone / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000096:biosynthesis / Q000235:genetics*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology; D015533:Transcriptional Activation
D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D016329:Sp1 Transcription Factor; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase