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RESEARCH PRODUCT
Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle.
Timo TakalaMia HorttanainenHarri SuominenEija PöllänenSarianna SipiläJukka PuolakkaVuokko KovanenPaula H. A. Ronkainensubject
estradioliTranscription GeneticEndocrinology Diabetes and MetabolismMuscle Fibers SkeletalEstrogen receptorpostmenopausal womenMuscle ProteinsFOXO1Receptor IGF Type 10302 clinical medicineEndocrinologyProtein IsoformsTestosteroneInsulin-Like Growth Factor IReceptorRandomized Controlled Trials as Topic0303 health sciencesEstradiolMyogenesisForkhead Box Protein O1TOR Serine-Threonine KinasesEstrogen Replacement TherapyForkhead Box Protein O3Forkhead Transcription FactorsMiddle Agedmedicine.anatomical_structureReceptors EstrogenReceptors AndrogenFemalemedicine.medical_specialtynorethisterone acetate030209 endocrinology & metabolismBiologypostmenopausaalinen nainen03 medical and health sciencesInternal medicinemedicineHumansnoretisteroniasetaattiluurankolihasskeletal muscleMuscle SkeletalProtein kinase BPI3K/AKT/mTOR pathway030304 developmental biologyhormonikorvaushoitoSKP Cullin F-Box Protein LigasesSkeletal muscleAndrogen receptorNorethindrone AcetateEndocrinologyHormone replacement therapyIGF-1 signalointiNorethindroneIGF-1 signalingProto-Oncogene Proteins c-aktdescription
Objectives To investigate the effects of combined hormone replacement therapy (HRT) and its effective agents on the IGF-1 signaling pathway. Design and methods To examine the effects of HRT on skeletal muscle in vivo, we utilized pre- and post-intervention samples from a randomized double blinded trial with 50–57-year-old women. The intervention included the year-long use of either HRT preparation (2 mg 17β-estradiol, E2; 1 mg norethisterone acetate, NETA, n = 10) or placebo (CO, n = 9). Microarray technology and quantitative PCR (qPCR) were used to study the expression of insulin-like growth factor I (IGF-1) and its splice variants as well as IGF-1 receptor, Akt1, mTOR, FOXO1, FOXO3, atrogin, estrogen receptors and androgen receptor in muscle samples. Serum concentrations of IGF-1, E2 and testosterone were measured. C2C12 myotubes were fed with E2 or NETA followed by analyzing the expression of essentially the same gene transcripts as in human samples by qPCR and phosphorylation of Akt and mTOR by Western blotting. Results The gene expression of IGF-1 and its splice variant, IGF-1Ec (also known as the mechano growth factor or MGF), mTOR, FOXO3, and AR was up-regulated among the HRT users compared to the CO (P < 0.05), while Akt1 was down-regulated (P < 0.05). The change in the level of IGF-1Ec transcript correlated positively with muscle size at post-intervention (r = 0.5, P < 0.05). In C2C12 myotubes, no statistically significant effects of either E2 or NETA at the level of gene transcripts studied were identified. The amount of phosphorylated Akt appeared to respond to NETA, albeit the response was not statistically significant. Phosphorylation of mTOR did not respond to either of the treatments. Conclusion Year-long postmenopausal HRT was found to affect the expression of the genes along the IGF-1 signaling cascade reflecting the higher muscle mass compared to the CO women. By using cell culture model we were, however, unable to confirm the possible differential role of E2 and NETA. It appears that the synchronous presence of both effective agents of the HRT or the presence of yet unidentified microenvironmental factors providing proper paracrine signals naturally existing in the intact muscle tissue is critical for appropriate signaling via sex steroid-IGF-1 axis to occur. peerReviewed
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2010-01-01 | Growth hormoneIGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society |