Estrogen Regulates the Satellite Cell Compartment in Females

Abstract

SUMMARY Skeletal muscle mass, strength, and regenerative capacity decline with age, with many measures showing a greater deterioration in females around the time estrogen levels decrease at menopause. Here, we show that estrogen deficiency severely compromises the maintenance of muscle stem cells (i.e., satellite cells) as well as impairs self-renewal and differentiation into muscle fibers. Mechanistically, by hormone replacement, use of a selective estrogen-receptor modulator (bazedoxifene), and conditional estrogen receptor knockout, we implicate 17β-estradiol and satellite cell expression of estrogen receptor α and show that estrogen signaling through this receptor is necessary to prevent apoptosis of satellite cells. Early data from a biopsy study of women who transitioned from peri- to post-menopause are consistent with the loss of satellite cells coincident with the decline in estradiol in humans. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.

Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

“…However, they found no difference in strength loss between E2-treated and untreated 20 month-old female mdx mice after 9 ECC indicating that E2 is not protective to muscle when challenged simultaneously by aging and dystrophin deficiency [ 49 ]. Indeed, recovery of strength was impaired in OVX mdx mice relative to sham mdx mice in the current study, consistent with our previous work in wild-type (WT) mice demonstrating that OVX mice recovered ~20% less isometric torque 1–3 weeks after injury compared to sham mice or E2-treated OVX mice [ 34 , 35 , 50 , 51 ].…”

“…Salimena et al found in 6 week-old mdx mice, that OVX mdx mice had decreased regenerating fibers compared to control female mdx mice [53]. This decrease in regenerating fibers in OVX mice supports the notion that estrogen deficiency compromises the ability of skeletal muscles to functionally recover after injury in mdx and WT female mice [34,35,50].…”

“…Satellite cells upon a stimulus, such as an injury, are activated, proliferate, differentiate, and either fuse to each other to form new muscle fibers or to existing muscle fibers. We, among other labs, have shown that estrogen deficiency causes a decline in satellite cell number in muscles of female mice [ 50 , 52 ]. Few studies have investigated the impact of estrogen on regeneration in dystrophin-deficient muscle.…”

Methodological Considerations for Studies in Sport and Exercise Science with Women as Participants: A Working Guide for Standards of Practice for Research on Women

“…In addition to reproductive function, ovarian steroids have been shown to target a number of tissues (e.g., epithelial, connective, muscle and nervous; [ 2 – 4 ]) and influence an array of biological processes (e.g., metabolism, ventilation, immunity, cognition, gastrointestinal, cardiovascular, autonomic regulation, and genitourinary function; [ 5 – 13 ]). As such, different concentrations of circulating ovarian steroids throughout the lifespan and across the menstrual cycle (with and without dysfunction and/or manipulation) might significantly influence the mechanisms that control and regulate cell function and integrated physiologic adaptation in women.…”

Sarcopenia and Menopause: The Role of Estradiol

“…Sarcopenic obesity has direct consequences on the health of menopausal and post-menopausal women (12). Interestingly, estradiol is also involved in the modulation of the local and systemic inflammatory responses thus affecting sarcopenia (13,14).…”