Voluntary wheel running and lithium supplementation improves muscle force production without altering SERCA function in the D2 mdx mouse

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease that, with no cure, leads to early mortality (30-40 years of age). Previous studies have shown that voluntary wheel running can mitigate disease pathology and improve muscle contractility in the preclinical mdx mouse model. We have shown that treating wild-type (WT) mice with a low dose of lithium, a natural inhibitor of glycogen synthase kinase 3, enhanced soleus (SOL) and extensor digitorum longus (EDL) muscle contractility. Our objectives were to test our hypothesis of whether combining VWR with low dose lithium supplementation could provide further benefits to muscle contractility in DBA/2J mdx mice – a model that displays far worse disease severity compared with the traditional C57BL/10 mdx mouse. We also examined if this combined intervention could improve muscle calcium regulation in muscle by assessing sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) function as we have recently shown that SERCA function is drastically impaired in D2 mdx mice, which could also contribute to deficits in muscle force production. Methods: Young (5-6 week old) male D2 WT and mdx mice were ordered from Jackson Laboratory. D2 mdx mice were assigned into each of the following conditions: sedentary ( mdxSED), voluntary wheel running ( mdxVWR), or VWR+lithium chloride ( mdxVWR+Li). The VWR groups were given access to a cagewheel for a total of 6 weeks, and the mdxVWR+Li group were provided a low dose of LiCl (50 mg/kg/day) via drinking water for the entire duration of the study. After 6 weeks, all mice were euthanized and the SOL and EDL muscles were subjected to force-frequency curve analysis (1-160 Hz). SERCA function was assessed by performing SERCA activity assays and a Ca 2+ uptake assay. Results: In the SOL, the combined effect of lithium and VWR improved specific force production to near WT levels across submaximal and maximal frequencies. Specific force production in the mdxVWR+Li group was significantly greater compared to the mdxSED group at all stimulation frequencies. Rate of SOL force development was significantly lower in all mdx groups compared to WT. However, rate of relaxation was only significantly reduced (vs. WT) within the mdxSED group, suggesting that VWR and VWR+Li improved relaxation. This could not be explained by any changes in SERCA function. In the EDL, specific force was significantly (p<0.001) reduced across mdx groups compared to WT; however, of all mdx groups, the mdxVWR+Li produced the most force and was significantly different compared to mdxVWR at 80 and 160 Hz. Rates of force development and relaxation were all slower in all mdx groups compared to WT, and there were no differences in SERCA activity. Conclusions: Combining lithium supplementation with VWR improved SOL and EDL force production in the D2 mdx mouse without any changes to SERCA function. V.A.F is a Tier 2 Canada Research Chair in Muscle Plasticity and Tissue-Remodelling. 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.