Estrogen Regulates the Satellite Cell Compartment in Females

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. Collins et al. show the loss of estrogen in female mice and post-menopausal women leads to a decrease in skeletal muscle stem cells. Using muscle stem cell-specific mutants, it was demonstrated that ERα is necessary for satellite cell maintenance, self-renewal, and protection from apoptosis, thereby promoting optimal muscle regeneration.