title: Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs.
abstract: MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.
authors.affiliation: Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy; Department of Clinical Pathology and Innovative Therapy, Advanced Technology Center for Aging Research, INRCA-IRCCS, Ancona, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Olivieri
authors.forename: Maarit
authors.initials: M
authors.lastname: Ahtiainen
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lazzarini
authors.forename: Eija
authors.initials: E
authors.lastname: Pöllänen
authors.forename: Miriam
authors.initials: M
authors.lastname: Capri
authors.forename: Maria
authors.initials: M
authors.lastname: Lorenzi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fulgenzi
authors.forename: Maria C
authors.initials: MC
authors.lastname: Albertini
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Alen
authors.forename: Urho M
authors.initials: UM
authors.lastname: Kujala
authors.forename: Giulia
authors.initials: G
authors.lastname: Borghetti
authors.forename: Lucia
authors.initials: L
authors.lastname: Babini
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Sarianna
authors.initials: S
authors.lastname: Sipilä
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.forename: Vuokko
authors.initials: V
authors.lastname: Kovanen
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Procopio
mesh_terms: D000367:Age Factors; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D017698:Postmenopause / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014430:Twins, Monozygotic
chemical_list: D007334:Insulin-Like Growth Factor I; D035683:MicroRNAs; C555159:MIRN142 microRNA, human; C525067:MIR223, human; C538984:Mirn182 microRNA, human
keywords: AKT; FOXO3A; IGF-1 signaling; IGF-1R; aging; mTOR; menopause; miR-142-3p; miR-182; miR-223; phosphorylation