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

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 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. 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.