Combined effects of lithium supplementation and exercise on memory in the D2 mdx mouse

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that occurs in 1 in 3500 boys. With muscular deficits, approximately one third of patients experience cognitive difficulties, including memory loss. Recently, it was found that DBA/2J (D2) mdx mice present with memory deficits and an increased presence of Alzheimer’s disease (AD)-like markers. A common contributor to AD pathology is glycogen synthase kinase 3 (GSK3), which promotes the production of amyloid beta (Aβ) via an increase in beta secretase 1 (BACE1) content and activity. Additionally, GSK3β has been shown to limit the expression and activation of the sarco(endo)plasmic reticulum calcium (Ca 2+ ) ATPase (SERCA), which also pathologically contributes to AD via increased free cytosolic Ca 2+ and neurodegeneration. Aerobic exercise in preclinical models of AD have been shown to inhibit GSK3 and reduce BACE1 activity; however, its effects on the mdx brain remains unknown. Furthermore, whether GSK3 in combination with exercise can provide additional cognitive benefits for the mdx mouse remains unknown. Here, we examined the effects of 6 weeks of voluntary wheel running (VWR) with and without the supplementation of low dose lithium, a natural GSK3 inhibitor. We hypothesized that aerobic exercise combined with lithium supplementation (VWR+Li) would provide the most cognitive benefit via a reduction in BACE1 activity and an enhancement in SERCA activity. Methods: 5-6 weeks old mice were separated into four groups: 1) wild-type (WT) healthy controls, 2 ) mdx sedentary, 3 ) mdx VWR, and 4 ) mdx VWR+Li (50 mg/kg/day lithium chloride via drinking water). An automated novel object recognition test (NORT) was conducted on the 5th week of training. At the time of euthanasia, hippocampal and prefrontal cortex (PFC) samples were collected. All samples were subjected to BACE1 and SERCA activity assays. Results: Automated NORT analysis showed that the VWR+Li mdx mice had higher investigation times compared to the mdx sedentary group ( p < 0.05), four hours post-training, similar to WT healthy controls. In the hippocampus, the mdx VWR+Li group had lower BACE1 activity compared to the mdx sedentary group; however, VWR alone could not elicit a similar effect, despite the fact VWR+Li ran less than VWR alone ( p < 0.05). Furthermore, maximal SERCA activity was higher in the VWR+Li mdx group compared to all other groups ( p < 0.05). In the PFC, no differences in BACE1 nor SERCA activity were found between the experimental groups. Conclusions: The combined therapy of VWR and lithium supplementation in mdx mice attenuated memory deficits, which was associated with lowered BACE1 activity and elevated maximal SERCA activity in the hippocampus. This work reveals exercise in conjunction with GSK3β inhibition as a potential therapeutic for DMD. CIHR and CRC to VAF. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.