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

Authors

  • Fabiola Olivieri,

    1. Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy
    2. Department of Clinical Pathology and Innovative Therapy, Advanced Technology Center for Aging Research, INRCA-IRCCS, Ancona, Italy
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    • Authors contributed equally to the manuscript.
  • Maarit Ahtiainen,

    1. Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
    2. Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
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    • Authors contributed equally to the manuscript.
  • Raffaella Lazzarini,

    1. Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy
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    • Authors contributed equally to the manuscript.
  • Eija Pöllänen,

    1. Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
    2. Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
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    • Authors contributed equally to the manuscript.
  • Miriam Capri,

    1. Department of Experimental Pathology, University of Bologna, Bologna, Italy
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  • Maria Lorenzi,

    1. Department of Experimental and Clinical Medicine, Division of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Ancona, Italy
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  • Gianluca Fulgenzi,

    1. Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy
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  • Maria C. Albertini,

    1. Dipartimento di Scienze Biomolecolari, Sezione di Biochimica e Biologia molecolare, Università degli Studi di Urbino “Carlo Bo”, Urbino, Italy
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  • Stefano Salvioli,

    1. Department of Experimental Pathology, University of Bologna, Bologna, Italy
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  • Markku J. Alen,

    1. Department of Medical Rehabilitation, Oulu University Hospital and Institute of Health Sciences, University of Oulu, Oulu, Finland
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  • Urho M. Kujala,

    1. Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
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  • Giulia Borghetti,

    1. Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy
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  • Lucia Babini,

    1. Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy
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  • Jaakko Kaprio,

    1. Department of Public Health, University of Helsinki, Helsinki, Finland
    2. Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
    3. National Institute for Health and Welfare, Helsinki, Finland
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  • Sarianna Sipilä,

    1. Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
    2. Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
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  • Claudio Franceschi,

    1. Department of Experimental Pathology, University of Bologna, Bologna, Italy
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  • Vuokko Kovanen,

    Corresponding author
    1. Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland
    2. Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
    • Correspondence

      Associate Professor Vuokko Kovanen, Department of Health Sciences, P.O Box 35; 40014- University of Jyväskylä, Finland. Tel.: +358 40 8053566; fax: +358 14 2602011; e-mail: vuokko.kovanen@jyu.fi

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  • Antonio D. Procopio

    1. Department of Clinical and Molecular Sciences, Division of Pathology, Università Politecnica delle Marche, Ancona, Italy
    2. Department of Clinical Pathology and Innovative Therapy, Advanced Technology Center for Aging Research, INRCA-IRCCS, Ancona, Italy
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  • [Correction added on 7 August 2014, after first online publication: miR-233 was corrected to miR-223 in both the title and keywords of the article.]

Summary

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.

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