Estradiol deficiency and skeletal muscle apoptosis: Possible contribution of microRNAs

Sira Karvinen, Hanna Kaarina Juppi, Gengyun Le, Christine A. Cabelka, Tara L. Mader, Dawn A. Lowe, Eija K. Laakkonen

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Menopause leads to estradiol (E2) deficiency that is associated with decreases in muscle mass and strength. Here we studied the effect of E2 deficiency on microRNA (miR) signaling that targets apoptotic pathways. Methods: C57BL6 mice were divided into control (normal estrous cycle, n = 8), OVX (E2 deficiency, n = 7) and OVX + E2 groups (E2-pellet, n = 4). Six weeks following the OVX surgery, mice were sacrificed and RNA isolated from gastrocnemius muscles. miR-profiles were studied with Next-Generation Sequencing (NGS) and candidate miRs verified using qPCR. The target proteins of the miRs were found using in silico analysis and measured at mRNA (qPCR) and protein levels (Western blot). Results: Of the apoptosis-linked miRs present, eleven (miRs-92a-3p, 122-5p, 133a-3p, 214-3p, 337-3p, 381-3p, 483-3p, 483-5p, 491-5p, 501-5p and 652-3p) indicated differential expression between OVX and OVX + E2 mice in NGS analysis. In qPCR verification, muscle from OVX mice had lower expression of all eleven miRs compared with OVX + E2 (p < 0.050). Accordingly, OVX had higher expression of cytochrome C and caspases 6 and 9 compared with OVX + E2 at the mRNA level (p < 0.050). At the protein level, OVX also had lower anti-apoptotic BCL-W and greater pro-apoptotic cytochrome C and active caspase 9 compared with OVX + E2 (p < 0.050). Conclusion: E2 deficiency downregulated several miRs related to apoptotic pathways thus releasing their targets from miR-mediated suppression, which may lead to increased apoptosis and contribute to reduced skeletal muscle mass.

Original languageEnglish (US)
Article number111267
JournalExperimental Gerontology
Volume147
DOIs
StatePublished - May 2021
Externally publishedYes

Bibliographical note

Funding Information:
This project was funded by the Academy of Finland (grants 309504 , 314181 and 335249 to EKL) and NIH grants R01 AG031743 and R01 AG062899 (to DAL). GL was supported by T32 AR050938, CAC by T32 AR007612, and TLM by T32 AG029796.

Publisher Copyright:
© 2021 The Authors

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • Caspase
  • Cytochrome C
  • Menopause
  • Muscle mass
  • Ovariectomy

PubMed: MeSH publication types

  • Journal Article

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