Low-Dose Lithium Supplementation Augments Mitochondrial Biogenesis In Murine Skeletal Muscle After High Fat Feeding

Promotion of oxidative metabolism in skeletal muscle improves muscle performance, fatigue resistance, and may help combat the obesogenic effects of a high fat diet. Lithium is a well-known glycogen synthase kinase (GSK3) inhibitor and we have recently shown that low-dose lithium supplementation (10 mg kg-1 day-1) augments skeletal muscle oxidative capacity in mice. In the soleus muscle, lithium mediated GSK3 inhibition increased the expression of oxidative markers such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and myosin heavy chain I (MHCI) leading to improvements in muscle contractility and fatigue resistance. Interestingly, this same dose of lithium (10 mg kg-1 day-1) has been previously shown to attenuate high fat diet induced weight gain and metabolic efficiency (weight gained per calories consumed). However, the impact of lithium supplementation on muscle oxidative phenotype after high fat feeding has yet to be investigated. In this study, 36 wild-type male C57BL/6J mice were randomly assigned to low-fat standard chow diet (LFD, 4% kcal fat), high-fat diet (HFD, 60% kcal fat), or HFD with lithium chloride (HFD + Li; 10 mg kg-1 day-1) treatment groups for 12 weeks. Soleus muscles were collected at the end for Western blot analysis of total and phosphorylated GSK3 (inhibitory sites serine9 for GSK3b and serine21 for GSK3a), PGC-1a, cytochrome c oxidase subunit IV (COXIV), and MHCI protein content. Our results showed that the level of phosphorylated GSK3a and GSK3b (relative to total GSK3) were significantly lower after the HFD (-41 and -44%, respectively, p < 0.05), but in the HFD + Li group levels were similar to the LFD group. Therefore, the HFD enhanced soleus muscle GSK3 activation, and lithium supplementation was able to reduce this effect. No significant changes in MHCI content were observed. When examining PGC-1a, we found that the HFD + Li group had protein levels that were nearly 2-fold higher vs LFD, albeit only trending towards significance (p = 0.06). Further, COXIV content progressively increased from LFD, to HFD, and to HFD + Li (linear trend, r2=0.26, p = 0.002) with both HFD and HFD + Li groups having significantly higher COXIV content when compared to LFD. Altogether, our data shows that GSK3 inhibition via low dose lithium supplementation can augment mitochondrial biogenesis in the presence of a HFD. Future studies will further examine whether GSK3 inhibition via lithium can augment muscle oxidative metabolism after high fat feeding.