Characterizing the association of systemic estradiol levels and transcriptional markers of skeletal muscle regeneration in healthy young females

Recent research indicates estradiol's (E2) role in modulating skeletal muscle regeneration. E2 has been observed to enhance myogenic capacity by upregulating myogenic factors and downregulating proteolytic factors1,2. The extracellular matrix (ECM) of skeletal muscle also influences regeneration due to its interaction with muscle progenitor cells 5. Cell and animal studies observed E2's ability to impact on collagen (COL) 1, 3, and 4 production 3,4. However, limited data from physiologically relevant human models exploring myogenic markers and ECM throughout the menstrual cycle are available. We hypothesize that higher systemic E2 levels will correspond to an increased regenerative gene expression signature. Understanding this relationship is crucial for assessing how E2 levels affect muscle healing in eumenorrheic women and E2’s potential as a therapeutic molecule for enhancing muscle repair. The study included 19 pre-menopausal women aged 18-39 undergoing hip surgery at UT Southwestern (UTSW) Medical Center. This study was approved by the UTSW IRB and conducted in accordance with the Declaration of Helsinki. Blood and muscle biopsies were collected for hormone and gene analysis. Only subjects in the follicular phase (n=12) were included to minimize progesterone's influence. Investigated genes included myogenic factors (MYOD1, MYF5, MYF6, MYOG), proteolytic factors (FOXO3, MuRF1), and COL genes (COL1a1, COL-3a1, COL-4a1, COL-6a1). E2 levels ranged from 26-356 pg/mL, with negligible progesterone levels, consistent with the follicular phase. While no significant relationships were found between myogenic and proteolytic genes, MYF6 exhibited a positive relationship with E2 (p=0.07), while MuRF1 showed a negative one (p=0.09). COL 1, 3, and 6 gene expressions had no significant relationship with E2, but COL 4 exhibited a statistically significant positive relationship (p=0.04) with E2 concentration. Though no statistically significant relationships emerged between myogenic or proteolytic gene expression and E2 levels, there were notable trends toward significance for MYF6 and MuRF1. MYF6, recognized for its role in myogenic differentiation, is implicated in maintaining the satellite cell pool by promoting myokine secretion6. In contrast, MuRF1 is a critical component in muscle atrophy7. COL4 expression was significantly associated with E2 levels (p=0.4). It is hypothesized that COL4 enhances IGF1-activated myoblast migration, differentiation, and fusion 5. These findings suggest a potential link between elevated E2 levels and an enhanced regenerative capacity. These findings indicate that higher E2 conditions may create a favorable environment for muscle recovery. Future research should increase sample size and examine protein levels of these factors. References: 1. Oxfeldt, M. et al.J. Appl. Physiol 2020. 2 Dieli-Conwright et al. J. Appl. Physiol 2009. 3. Fede, C. et al. PLoS One 2019. 4. Seko, D. et al. Stem Cell Reports 2020. 5. Ito, A. et alJ. Biosci. Bioeng.2015.6. Lazure, F. et al. EMBO Rep. 2020 7. Peris-Moreno et al. Int. J. Mol. Sci. 2020. This study was funded by NIAMS 1R01AR069176-01A1 and NIH diversity supplement: 1R01AR069176-01S. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.