Can low-dose lithium supplementation protect against sarcopenic obesity in ovariectomized mice?

Abstract

During menopause, females lose the protective effects of estrogen and are at risk for age-related diseases, including sarcopenic obesity. Sarcopenic obesity is the coexistence of excess adiposity and muscle atrophy and weakness that is associated with age. Glycogen synthase kinase 3 (GSK3) is a well-known negative regulator of muscle mass, strength, and the oxidative fibre type, and has been associated with weight gain and obesity. Our lab has found that inhibiting GSK3 using low-dose lithium (Li) supplementation improves skeletal muscle function, elevates whole-body energy expenditure, and enhances insulin sensitivity in male mice. However, it is unknown whether GSK3 inhibition will have similar benefits in female mice in the presence and absence of estrogen. The purpose of this thesis was to investigate whether low-dose Li supplementation can protect against sarcopenic obesity in ovariectomized (OVX) mice. 28-week-old sham and OVX C57BL/6J mice were divided into a control (con) or Li group, giving rise to four groups: sham-con, OVX-con, sham-Li, and OVX-Li (n = 6-10 per group). OVX-Li mice were provided a dose of 50 mg/kg/day of Li via drinking water for 8 weeks. Energy expenditure was higher in Li-treated mice compared to control mice. However, this increase in energy expenditure did not alter body composition. Force production of soleus and EDL were significantly lower in OVX-con mice compared to sham-con. Li supplementation increased force production of soleus and EDL in OVX mice. Muscle fatigability was improved in soleus, but not EDL, of sham and OVX mice provided with Li supplementation. Glucose handling and insulin sensitivity were not affected by Li treatment, however, fasting blood glucose levels were improved with Li supplementation in OVX mice. OVX-Li mice had greater cage activity than OVX-con mice, which suggests improved muscle function. OVX mice had lower bone mineral density than sham mice, however, this was increased with Li supplementation. In conclusion, low-dose Li supplementation did not alter body composition or glucose handling in OVX mice, but did improve force production, fatigue resistance, energy expenditure, fasting blood glucose levels, cage activity, and BMD, suggesting that GSK3 inhibition may protect against muscle weakness associated with estrogen loss.