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

Abstract

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 ERα-knockout mice exhibit numerous biological disorders, but little is known regarding the specific role of ERα in skeletal muscle contractile function. The purpose of this study was to determine the impact of skeletal muscle-specific ERα deletion on contractile function, hypothesizing that ERα is a main receptor through which estradiol affects muscle strength in females. Deletion of ERα 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.

Comparative Transcriptome and Methylome Analysis in Human Skeletal Muscle Anabolism, Hypertrophy and Epigenetic Memory

“…(estrogen receptor 1) in the present study was hypermethylated with reduced gene expression in the young adult males after acute RE, whereas in female mice after knock-down, it has been shown to cause muscle weakness 49 yet, overexpression can result in a slow muscle fibre phenotype 50 . Therefore, a reduction observed in the adult males may therefore be associated with reduced slow fibre formation and subsequently may be conducive to faster fibre formation, previously identified to occur after resistance exercise.…”

The impact of ERα action on muscle metabolism and insulin sensitivity – Strong enough for a man, made for a woman

“…Whether defects in exercise training are linked with impaired mitochondrial function and disruption of calcium homeostasis is unclear. In addition to diminished muscular endurance in MERKO, Lai and Collins showed that ERα deficient muscles are also fast fatiguing and have reduced performance capability [165] , [166] ( Figure 6 ). Studies from this group show that E 2 , in a concentration-dependent manner, elevates phosphorylation of the myosin regulatory light chain (pRLC) in C2C12 myotubes in culture and in muscles from C57BL/6J mice [166] .…”

“…In addition to diminished muscular endurance in MERKO, Lai and Collins showed that ERα deficient muscles are also fast fatiguing and have reduced performance capability [165] , [166] ( Figure 6 ). Studies from this group show that E 2 , in a concentration-dependent manner, elevates phosphorylation of the myosin regulatory light chain (pRLC) in C2C12 myotubes in culture and in muscles from C57BL/6J mice [166] . Female mice with a skeletal muscle-specific KO of ERα produced 16% less eccentric and 16–26% less submaximal and maximal isometric force with impaired force recovery relative to WT mice.…”

Non-invasive Assessment of Dorsiflexor Muscle Function in Mice

“…The clamp also avoids potential inflammation that a trans-osseous pin might create, while still allowing accurate assessment of muscle contractility. Furthermore, the mouse knee clamp has been successfully used 14 . 5.…”