Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle
Open accessAbstract
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; 1mg 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, E(2) 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.
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Recent studies suggest a beneficial role for hormone replacement therapy (HRT), supplementation with estrogen and progesterone, and the induction of pathways by which estrogen can aide in skeletal muscle maintenance and repair.
“Recent studies suggest a beneficial role for hormone replacement therapy (HRT), supplementation with estrogen and progesterone, and the induction of pathways by which estrogen can aide in skeletal muscle maintenance and repair (71).”
From Sex-Based Differences in Skeletal Muscle Kinetics and Fiber-Type Composition (2015) · cites this paper as [71]
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- Authors
- Pöllänen, E., Ronkainen, P. H. A., Horttanainen, M., Takala, T., Puolakka, J., Suominen, H., Sipilä, S., & Kovanen, V.
- Affiliations
- University of Jyväskylä (FI)
- Oulu Deaconess Institute (FI)
- Central Finland Health Care District (FI)
- Corresponding author
- Kovanen, Vuokko
- Venue
- Growth Hormone & IGF Research
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 20
- Issue
- 5
- Pages
- 372-379
- ISSN
- 1096-6374 (ISSN-L)
- OpenAlex
- W1975249345
- Cited by
- 54
- References
- 59
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 5 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 8 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 1
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- green
- urn.fi
- Locations
- Growth Hormone & IGF Research (publishedVersion)
- PubMed (publishedVersion)
- Jyväskylä University Digital Archive (University of Jyväskylä) (submittedVersion)
- Funders
- Seventh Framework Programme (GA-223576)
- Suomen Kulttuurirahasto
- Opetus- ja Kulttuuriministeriö
- Academy of Finland
- Jenny ja Antti Wihurin Rahasto
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- combined hormone replacement therapy, IGF-1 signaling, skeletal muscle, postmenopausal women, estradiol, norethisterone acetate, mechano growth factor, IGF-1 receptor, AKT1, mTOR, FOXO3, androgen receptor, estrogen receptor, muscle mass, C2C12 myotubes
- MeSH terms
- Forkhead Box Protein O1, Forkhead Box Protein O3, Norethindrone Acetate, Estradiol, Female, Humans, Insulin-Like Growth Factor I, Middle Aged, Muscle Proteins, Norethindrone, Receptors, Androgen, Receptors, Estrogen, Testosterone, Transcription, Genetic, Estrogen Replacement Therapy, Randomized Controlled Trials as Topic, Receptor, IGF Type 1, Muscle, Skeletal, Muscle Fibers, Skeletal, Protein Isoforms, SKP Cullin F-Box Protein Ligases, Proto-Oncogene Proteins c-akt, Forkhead Transcription Factors, TOR Serine-Threonine Kinases
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