["The Journal of Physiology, Volume 604, Issue 7, Page 2845-2866, 1 April 2026. ", "\nAbstract figure legend Low‐dose lithium supplementation in ovariectomized mice enhances skeletal muscle contractility (isometric force and fatigue resistance), SERCA function and promotes favourable transcriptional reprogramming, while increasing bone density and modestly improving insulin sensitivity.\n\n\n\n\n\n\n\n\n\nAbstract\nPostmenopausal women have an increased risk for age‐related conditions like sarcopenia, osteoporosis and type 2 diabetes. Here we examined the effects of low‐dose lithium (Li) supplementation, a well‐known glycogen synthase kinase 3 (GSK3) inhibitor, on ovariectomized (OVX) mice, focusing on muscle strength and endurance, bone mineral density (BMD) and insulin sensitivity. 28‐week‐old female sham and OVX C57BL/6J mice were divided into three groups: sham, OVX and OVX‐Li, with the latter receiving 50 mg/kg/day of Li in their drinking water for 8 weeks. Li supplementation enhanced isometric specific force and fatigue resistance of the soleus and extensor digitorum longus (EDL) muscles. Potential cellular mechanisms underlying these benefits include enhanced Ca2+ uptake, lowered oxidative stress, increased expression of select mitochondrial markers and a blunted muscle transcriptomic response to OVX surgery with Li supplementation. OVX mice exhibited lower BMD than sham controls; however Li supplementation restored BMD levels. Finally Li supplementation yielded modest improvements in insulin tolerance. In conclusion our findings highlight the advantages of low‐dose Li for musculoskeletal and metabolic health in OVX female mice.\n\n\n\n\n\n\n\n\n\nKey points\n\nOvariectomy surgery compromises musculoskeletal and metabolic health in female mice.\nHere, we explored the potential benefits of low‐dose lithium (Li) treatment.\nLi improved muscle isometric force production and fatigue resistance.\nRNA‐Seq demonstrated that Li blunted the effects of OVX surgery.\nLi supplementation increased bone mineral density and insulin tolerance.\n\n\n"]