Ablation of skeletal muscle estrogen receptor alpha impairs contractility in male mice

Estradiol and estrogen receptor alpha (ER alpha) have been shown to be important for the maintenance of skeletal muscle strength in females; however, little is known about the roles of estradiol and ER alpha in male muscle. The purpose of this study was to determine if skeletal muscle ER alpha is required for optimal contractility in male mice. We hypothesize that reduced ER alpha in skeletal muscle impairs contractility in male mice. Skeletal muscle-specific knockout (skmER alpha KO) male mice exhibited reduced strength across multiple muscles and several contractile parameters related to force generation and kinetics compared with wild-type littermates (skmER alpha WT). Isolated EDL muscle-specific isometric tetanic force, peak twitch force, peak concentric and peak eccentric forces, as well as the maximal rates of force development and relaxation were 11%-21% lower in skmER alpha KO compared with skmER alpha WT mice. In contrast, isolated soleus muscles from skmER alpha KO mice were not affected. In vivo peak torque of the anterior crural muscles was 20% lower in skmER alpha KO compared with skmER alpha WT mice. Muscle masses, contractile protein contents, fiber types, phosphorylation of the myosin regulatory light chain, and caffeine-elicited force did not differ between muscles of skmER alpha KO and skmER alpha WT mice, suggesting that strength deficits were not due to size, composition, or calcium release components of muscle contraction. These results indicate that in male mice, reduced skeletal muscle ER alpha blunts contractility to a magnitude similar to that previously reported in females; however, the mechanism may be sexually dimorphic. NEW & NOTEWORTHY We comprehensively measured in vitro and in vivo contractility of leg muscles with reduced estrogen receptor alpha (ER alpha) in male mice and reported that force generation and contraction kinetics are impaired. In contrast to findings in females, phosphorylation of myosin regulatory light chain cannot account for low force production in male skeletal muscle ER alpha knockout mice. These results indicate that ER alpha is required for optimal contractility in males and females but via sexually dimorphic means.