Estrogen signaling increases nuclear receptor subfamily 4 group A member 1 expression and energy production in skeletal muscle cells

Abstract

Estrogen deficiency has been known to associate with musculoskeletal diseases in women, based on the clinical observations of frequent susceptibility to osteoporosis and sarcopenia among postmenopausal women. In skeletal muscles, estrogen has been assumed to play physiological roles in maintaining muscle mass and strength, although its precise molecular mechanism remains to be elucidated. We have previously shown that estrogen regulates energy metabolism through the downregulation of mitochondrial uncoupling protein 3 (UCP3) in skeletal muscles, which may contribute to the prolonged exercise endurance in female mice. In the present study, we investigated the effects of estrogen on the expression levels of all members of the nuclear receptor superfamily. Microarray analysis showed that the mRNA level of nuclear receptor subfamily 4 group A member 1 (Nr4a1) was upregulated by the transduction of a recombinant adenovirus expressing constitutively active estrogen receptor α (caERα) in differentiated myoblastic C2C12 cells. Thus we assumed that NR4A1 may be an estrogen-inducible gene in myoblastic cells. We also demonstrated that caERα increases the cellular ATP content along with an increase in mitochondrial DNA content in differentiated myoblastic C2C12 cells. In contrast, the knockdown of Nr4a1 using siRNA exhibited reduced ATP generation as well as a decrease in mitochondrial DNA content. Overall, the present study indicates a crosstalk between estrogen signaling and NR4A1 in skeletal muscle cells. We consider that estrogendependent NR4A1 upregulation could increase efficient ATP generation in skeletal muscle cells partly through enhancing mitochondrial functions.

Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma—Possible Estrogen Effects

“…Inhibition of endogenous estrogen synthesis in the grafted mice using the aromatase inhibitor letrozole reduced the expression of all three NR4A family members. To note is that estrogen regulation of NR4A gene family members has been described in white adipose tissue and skeletal muscle cells [33,34]. Using the same criteria as above, an indication of estrogen regulation of NR4A expression in the GCB DLBCL could not be found, also stressing a difference in estrogen response between the ABC and GCB subtypes.…”

Roles of Estrogen, Estrogen Receptors, and Estrogen-Related Receptors in Skeletal Muscle: Regulation of Mitochondrial Function

“…Thus, estrogen may contribute to efficient ATP generation in mitochondria by blocking energy dissipation. Subsequently, nuclear receptor subfamily 4 group A member 1 (Nr4a1) was also demonstrated as an estrogen responsive gene in the caERα-overexpressed C2C12 cells [67]. Since NR4A1 stimulates the respiration of skeletal muscle mitochondria [68], NR4A1 may also mediate estrogen function in muscle.…”

Hormonal regulation of metabolism—recent lessons learned from insulin and estrogen

“…However, ERβ has been found to be localized in cancer cells' mitochondria, where it appears to influence the action of mitochondrial DNA or mitochondrial transcription factors [ 138 ]. Constant ERα overexpression increases cellular ATP content as well as mitochondrial DNA content in differentiated myoblastic C2C12 cells via nuclear receptor subfamily 4 group A member 1 (Nr4a1) activation ( Figure 2 A); however, the direct regulation of ERα on Nr4a1 at the transcriptional level requires further investigation [ 139 ]. It has been shown that palmitic acid treatment in cells or high fat diet intervention in animals impaired hepatic mitochondrial function, inducing oxidative stress and activation of c-Jun N-terminal kinase (JNK) which has been related to the development of insulin resistance and steatosis [ 140 ].…”