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.
Bibliographical noteFunding Information:
We thank Angus Lindsay, Vineesha Kollipara, Tara Mader, Mayank Verma, Alessandro Magli, Yi Ren, and Olivia Recht for technical assistance and Atsushi Asakura and Ken Korach/Andrea Hevener for the Pax7 CreERT2/+ ;R26R tdTomato mice and ERα floxed mice, respectively. Bazedoxifene was a gift from Pfizer. We thank the University of Minnesota Genomics Center for providing sequencing series for this paper. We thank Cynthia S. Faraday for graphic design. Our research has been supported by the NIH grants R01-AG031743 (D.A.L.), R01-AR055685 (M.K.), T32-AR007612 (B.C.C., R.W.A., C.W.B., and C.A.C.), and T32-AG0299796 (A.A.L.); the Muscular Dystrophy Association grant MDA351022 (M.K.); a grant from the American Diabetes Association BS-1-15-170 (E.E.S.); a grant from the Office of the Vice President for Research, University of Minnesota (D.A.L.); and grants from the Academy of Finland 275323 (V.K.) and 309504 (E.K.L.). B.C.C. was also supported by a University of Minnesota Interdisciplinary Doctoral Fellowship .
- muscle stem cells
- ovarian hormones
- skeletal muscle
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't