Estradiol deficiency in females can result in skeletal muscle strength loss, and treatment with estradiol mitigates the loss. There are three primary estrogen receptors (ERs), and estradiol elicits effects through these receptors in various tissues. Ubiquitous ER-knockout mice exhibit numerous biological disorders, but little is known regarding the specific role of ER- in skeletal muscle contractile function. The purpose of this study was to determine the impact of skeletal muscle-specific ER- deletion on contractile function, hypothesizing that ERα is a main receptor through which estradiol affects muscle strength in females. Deletion of ER- specifically in skeletal muscle (skmERαKO) did not affect body mass compared with wild-type littermates (skmERαWT) until 26 wk of age, at which time body mass of skmERαKO mice began to increase disproportionally. Overall, skmERαKO mice had low strength demonstrated in multiple muscles and by several contractile parameters. Isolated extensor digitorum longus muscles from skmERαKO mice produced 16% less eccentric and 16-26% less submaximal and maximal isometric force, and isolated soleus muscles were more fatigable, with impaired force recovery relative to skmERαWT mice. In vivo maximal torque productions by plantarflexors and dorsiflexors were 16% and 12% lower in skmERαKO than skmERαWT mice, and skmERαKO muscles had low phosphorylation of myosin regulatory light chain. Plantarflexors also generated 21-32% less power, submaximal isometric and peak concentric torques. Data support the hypothesis that ablation of ERα in skeletal muscle results in muscle weakness, suggesting that the beneficial effects of estradiol on muscle strength are receptor mediated through ERα. NEW & NOTEWORTHY We comprehensively measured in vitro and in vivo skeletal muscle contractility in female estrogen receptor α (ERα) skeletal muscle-specific knockout mice and report that force generation is impaired across multiple parameters. These results support the hypothesis that a primary mechanism through which estradiol elicits its effects on strength is mediated by ERα. Evidence is presented that estradiol signaling through ERα appears to modulate force at the molecular level via posttranslational modifications of myosin regulatory light chain.
Bibliographical noteFunding Information:
Our research has been supported by National Institutes of Health Grants R01 AG-031743 (D. A. Lowe), T32 AR-007612 (B. C. Collins and C. A. Cabelka), and T32 AG-0299796 (T. L. Mader); a grant from the Office of the Vice President for Research, University of Minnesota (D. A. Lowe); and a grant from the American Diabetes Association (BS-1-15-170, E. E. Spangen-burg). T. L. Mader and B. C. Collins were also supported by a University of Minnesota Doctoral Dissertation Fellowship and Interdisciplinary Doctoral Fellowship, respectively.
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- Hormone receptor
- Muscle physiology