Age related changes of cAMP and MAPK signaling in Leydig cells of Wistar rats

Age related changes of cAMP and MAPK signaling in Leydig cells of Wistar rats

Here, we chronologically analyzed age-associated changes of cAMP- and MAPK-signaling in Leydig cells (LCs) in relation with decreased testosterone (T) production. In Wistar rats, decreased serum T observed in 12 to 24-month-old rats was not related to decreased serum LH concentration but to reduced...

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Bibliographic Details
Published in:Experimental gerontology Vol. 58; pp. 19 - 29
Main Authors: Sokanovic, S.J., Janjic, M.M., Stojkov, N.J., Baburski, A.Z., Bjelic, M.M., Andric, S.A., Kostic, T.S.
Format: Journal Article
Language:English
Published: England Elsevier Inc 01-10-2014
Subjects:
AC10
Adenylyl Cyclases - metabolism
Age Factors
Aging
Aging - genetics
Aging - metabolism
Animals
Cellular Senescence
Cyclic AMP - metabolism
Enzyme Activation
Gene Expression Regulation, Enzymologic
Leydig cells
Leydig Cells - enzymology
Male
MAPK
Mitogen-Activated Protein Kinases - metabolism
PDEs
Phosphorylation
Rats
Rats, Wistar
RNA, Messenger - metabolism
Signal Transduction
Testosterone
Testosterone - blood
Insl3/INSL3
Nur77
BSA
Leydig cells
Aging
Hsd17b
Sf1
PBS
AC
Gsα
IBMX
ms
PKA
Cyp19
Prkaca
Prkacb
Gapdh
MAPK
ERK1/2
Lhr/LHR
Scarb1
P38
pJNK1
Actb/ACTB
Hsd3b/HSD3B
Gata4
M-199
Cyp17a/CYP17a
Prkar1a
PKAR
RQ-PCR
cAMP
hCG
Pde
Dax1/DAX1
DHT
Star/StAR
T
Dusp1
pERK1/2
GnRH
LCs
AC10
Cyp11a/CYP11a
KH-7
Prkar2a
Adcy
PDEs
DMEM/F12
RIA
pP38
Testosterone
8BrcAMP
Tspo
Creb/CREB
Mapk8/JNK1
LH
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Summary:Here, we chronologically analyzed age-associated changes of cAMP- and MAPK-signaling in Leydig cells (LCs) in relation with decreased testosterone (T) production. In Wistar rats, decreased serum T observed in 12 to 24-month-old rats was not related to decreased serum LH concentration but to reduced luteinizing hormone receptor (Lhr/LHR) and time-coordinated reduction of steroidogenic gene expression (decreased Cyp11a1, Cyp17a1 in 12-month-old rats followed by decreased Star/StAR, Hsd3b/HSD3B, Hsd17b4, and increased Cyp19a1 later in life). The predecessors of age-related changes noted in LCs from 6 to 12-month-old rats were increased level of soluble adenylate cyclase (Adcy/AC) 10, increased JNK phosphorylation but suppressed P38 MAPK. At approximately the same time changed mRNA abundance for transcription factors important for steroidogenesis was detected (increased Nur77 and decreased Sf1, Dax1). Aging caused biphasic expression pattern of ERK1/2 and Nur77: increased in 12-month but decreased in LCs from 24-month-old rats. Further, decreased basal cAMP level observed from 12 to 24th month coincidence with increased expression of cAMP-specific phosphodiesterase (Pde)4a, Pde4b and regulatory subunit of protein kinase A (Prkar/PKAR). Exposing of senescent LCs to permeable cAMP-analog improved transcription of Sf1, Nur77, Star, Cyp11a1,Cyp17a1, but without effect on aging pattern of Dax1, Pde4a/b, Prkar2a, Lhr and MAPK genes. Collectively, results indicated that age-related LC dysfunction is accompanied with changes in MAPK and cAMP signaling and coordinated reduction in the expression of many of the genes that participate in T synthesis. The predecessors of aged-related changes are increased ratio of pJNK/JNK, AC10 and decreased P38 level in LCs from 6-month-old rats. •Reduction of steroidogenic genes expression in time reflects Leydig cell aging.•Changes in MAPK and cAMP signaling precede age-related hypofunction of Leydig cells.•Activation of AC10 and JNK occurs prior to the reduction of testosterone production.•Age-related cAMP decrease in Leydig cell coincided with increased expression of Pde4.•The signals independent of cAMP contribute to Leydig cells steroidogenic failure.
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content type line 23
ISSN:0531-5565
1873-6815
DOI:10.1016/j.exger.2014.07.004