Deletion of estrogen receptor alpha in skeletal muscle results in impaired contractility in female mice

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 alpha-knockout mice exhibit numerous biological disorders, but little is known regarding the specific role of ER alpha in skeletal muscle contractile function. The purpose of this study was to determine the impact of skeletal muscle-specific ER alpha deletion on contractile function, hypothesizing that ER alpha is a main receptor through which estradiol affects muscle strength in females. Deletion of ER alpha specifically in skeletal muscle (skmER alpha KO) did not affect body mass compared with wild-type littermates (skmER alpha WT) until 26 wk of age, at which time body mass of skmER alpha KO mice began to increase disproportionally. Overall, skmER alpha KO mice had low strength demonstrated in multiple muscles and by several contractile parameters. Isolated extensor digitorum longus muscles from skmER alpha KO 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 skmER alpha WT mice. In vivo maximal torque productions by plantarflexors and dorsiflexors were 16% and 12% lower in skmER alpha KO than skmER alpha WT mice, and skmER alpha KO 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 ER alpha in skeletal muscle results in muscle weakness, suggesting that the beneficial effects of estradiol on muscle strength are receptor mediated through ER alpha. NEW & NOTEWORTHY We comprehensively measured in vitro and in vivo skeletal muscle contractility in female estrogen receptor alpha (ER alpha) 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 ER alpha. Evidence is presented that estradiol signaling through ER alpha appears to modulate force at the molecular level via posttranslational modifications of myosin regulatory light chain.