Low‐dose lithium supplementation promotes musculoskeletal and metabolic health in ovariectomized female mice

Abstract Postmenopausal 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 Ca 2+ 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. image Key points Ovariectomy surgery compromises musculoskeletal and metabolic health in female mice. Here, we explored the potential benefits of low‐dose lithium (Li) treatment. Li improved muscle isometric force production and fatigue resistance. RNA‐Seq demonstrated that Li blunted the effects of OVX surgery. Li supplementation increased bone mineral density and insulin tolerance.