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

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 of 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 alpha (caER alpha) in differentiated myoblastic C2C12 cells. Thus we assumed that NR4A1 may be an estrogen-inducible gene in myoblastic cells. We also demonstrated that caER alpha 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 estrogen-dependent NR4A1 upregulation could increase efficient ATP generation in skeletal muscle cells partly through enhancing mitochondrial functions.