Differential alterations in gene expression profiles contribute to time-dependent effects of nandrolone to prevent denervation atrophy.
BACKGROUND
Anabolic steroids, such as nandrolone, slow muscle atrophy, but the mechanisms responsible for this effect are largely unknown. Their effects on muscle size and gene expression depend upon time, and the cause of muscle atrophy. Administration of nandrolone for 7 days beginning either concomitantly with sciatic nerve transection (7 days) or 29 days later (35 days) attenuated denervation atrophy at 35 but not 7 days. We reasoned that this model could be used to identify genes that are regulated by nandrolone and slow denervation atrophy, as well as genes that might explain the time-dependence of nandrolone effects on such atrophy. Affymetrix microarrays were used to profile gene expression changes due to nandrolone at 7 and 35 days and to identify major gene expression changes in denervated muscle between 7 and 35 days.


RESULTS
Nandrolone selectively altered expression of 124 genes at 7 days and 122 genes at 35 days, with only 20 genes being regulated at both time points. Marked differences in biological function of genes regulated by nandrolone at 7 and 35 days were observed. At 35, but not 7 days, nandrolone reduced mRNA and protein levels for FOXO1, the mTOR inhibitor REDD2, and the calcineurin inhibitor RCAN2 and increased those for ApoD. At 35 days, correlations between mRNA levels and the size of denervated muscle were negative for RCAN2, and positive for ApoD. Nandrolone also regulated genes for Wnt signaling molecules. Comparison of gene expression at 7 and 35 days after denervation revealed marked alterations in the expression of 9 transcriptional coregulators, including Ankrd1 and 2, and many transcription factors and kinases.


CONCLUSIONS
Genes regulated in denervated muscle after 7 days administration of nandrolone are almost entirely different at 7 versus 35 days. Alterations in levels of FOXO1, and of genes involved in signaling through calcineurin, mTOR and Wnt may be linked to the favorable action of nandrolone on denervated muscle. Marked changes in the expression of genes regulating transcription and intracellular signaling may contribute to the time-dependent effects of nandrolone on gene expression.
Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J, Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, New York 10468, USA.
Weiping
W
Qin
Jiangping
J
Pan
William A
WA
Bauman
Christopher P
CP
Cardozo
D000818:Animals; D015153:Blotting, Western; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009121:Muscle Denervation; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation* / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics* / Q000517:prevention & control* / Q000601:surgery; D009277:Nandrolone / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D009124:Muscle Proteins; D012333:RNA, Messenger; D009277:Nandrolone