TY - JOUR
T1 - Estradiol deficiency and skeletal muscle apoptosis
T2 - Possible contribution of microRNAs
AU - Karvinen, Sira M
AU - Juppi, Hanna Kaarina
AU - Le, Gengyun C
AU - Cabelka, Christine A.
AU - Mader, Tara L.
AU - Lowe, Dawn A.
AU - Laakkonen, Eija K.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/5
Y1 - 2021/5
N2 - BACKGROUND: Menopause leads to estradiol (E
2) deficiency that is associated with decreases in muscle mass and strength. Here we studied the effect of E
2 deficiency on microRNA (miR) signaling that targets apoptotic pathways.
METHODS: C57BL6 mice were divided into control (normal estrous cycle, n = 8), OVX (E
2 deficiency, n = 7) and OVX + E
2 groups (E
2-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 + E
2 mice in NGS analysis. In qPCR verification, muscle from OVX mice had lower expression of all eleven miRs compared with OVX + E
2 (p < 0.050). Accordingly, OVX had higher expression of cytochrome C and caspases 6 and 9 compared with OVX + E
2 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 + E
2 (p < 0.050).
CONCLUSION: E
2 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.
AB - BACKGROUND: Menopause leads to estradiol (E
2) deficiency that is associated with decreases in muscle mass and strength. Here we studied the effect of E
2 deficiency on microRNA (miR) signaling that targets apoptotic pathways.
METHODS: C57BL6 mice were divided into control (normal estrous cycle, n = 8), OVX (E
2 deficiency, n = 7) and OVX + E
2 groups (E
2-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 + E
2 mice in NGS analysis. In qPCR verification, muscle from OVX mice had lower expression of all eleven miRs compared with OVX + E
2 (p < 0.050). Accordingly, OVX had higher expression of cytochrome C and caspases 6 and 9 compared with OVX + E
2 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 + E
2 (p < 0.050).
CONCLUSION: E
2 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.
KW - Caspase
KW - Cytochrome C
KW - Menopause
KW - Muscle mass
KW - Ovariectomy
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U2 - 10.1016/j.exger.2021.111267
DO - 10.1016/j.exger.2021.111267
M3 - Article
C2 - 33548486
AN - SCOPUS:85100629330
SN - 0531-5565
VL - 147
JO - Experimental Gerontology
JF - Experimental Gerontology
M1 - 111267
ER -