Selective estrogen receptor-β activation stimulates skeletal muscle growth and regeneration

There is increasing evidence suggesting that estrogens augment skeletal muscle regeneration processes after injury. To study the contribution of estrogen receptors α and β (ERα and ERβ) during muscle regeneration, skeletal muscles of ovariectomized (OVX) rats, as well as ERα- and ERβ-knockout (αErko and βErko) mice, were injured with a myotoxin (notexin). OVX rats were simultaneously treated with the ER-selective ligands genistein, ERα agonist 16α-LE2 (alpha), ERβ agonist 8β-VE2 (beta), or 17β-estradiol (E(2)). OVX rats showed significantly elevated serum creatine kinase (CK) activity after muscle injury compared to intact sham-treated animals. Treatment with ER ligands significantly reduced CK activity. TNF-α, IL-10, and MCP-1 expression served to characterize immune responses. Treatment with all ER ligands, but particularly E(2) and beta, reduced TNF-α, but elevated MCP-1 and IL-10 expression. PCNA and MyoD expression served to define satellite cell activation and proliferation and were found to be up-regulated by beta and E(2). To further study muscle regeneration responses, expression of the embryonic myosin heavy chain (MHC) was analyzed. Beta and E(2) but not alpha increased embryonic MHC expression compared to OVX. The absence of ERβ in βErko mice negatively affected CK activity levels and expression of satellite cell and muscle regeneration markers (MHC embryonic, MyoD, Pax7) compared with αErko and wild-type mice. In a classic Hershberger assay using male rats, beta stimulated muscle growth, accompanied by a strong induction of IGF-1 expression. Our data provide evidence that ERβ signaling is involved in the regulation of skeletal muscle growth and regeneration by stimulating anabolic pathways, activating satellite cells and modulating immune responses.