Voluntary wheel running and lithium supplementation promotes fatigue resistance, fat oxidation, and improves insulin tolerance in D2 mdx mice

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle wasting and premature death. Many DMD patients will also exhibit signs of metabolic dysfunction such as insulin resistance that predisposes them to type 2 diabetes and worsened cardiovascular disease. Most treatments for DMD aim to lower muscle inflammation and improve strength, however, none have addressed the complication of insulin resistance. The current standard of treatment is corticosteroids, which prolongs ambulation, however, chronic use increases susceptibility to obesity, insulin resistance, and type 2 diabetes. It is well-established that regular aerobic exercise enhances insulin sensitivity. Further, we have recently found that inhibiting glycogen synthase kinase 3 with lithium (Li), a known insulin mimetic, improves force production and fatigue resistance in wildtype (WT) mice. Here, we tested whether voluntary wheel running (VWR) and Li supplementation, together, could improve whole-body fatigue, metabolism, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. METHODS: 5-week old male D2 WT and mdx mice were separated into four groups: WT, mdx sedentary (SED), mdx VWR, and mdx Li+VWR (n=11/group). The mdx VWR and mdx Li+VWR mice had unlimited access to a cagewheel, and mdx Li+VWR mice were given a low dose of Li (50 mg/kg/day) via their drinking water throughout the study. A treadmill time-to-fatigue test was performed to assess whole-body fatigue. Mice were housed for 48-hours in metabolic cages to measure energy expenditure. Glucose handling was measured using glucose and insulin tolerance tests. RESULTS: As expected, WT mice had ~2-fold greater total cage activity compared to all mdx groups. When examining cagewheel distance, we found that mdx Li+VWR mice ran half the total distance in kilometres than mdx VWR mice (39.1 ± 9.6 km vs. 74.8 ± 13.6 km). Despite this, VWR with and without Li improved whole-body fatigue as only mdx SED mice (22.8 ± 0.9 min) had a shorter time to exhaustion than WT mice (32.6 ± 0.9 min). All mdx groups had higher energy expenditure than WT mice, suggestive of a hypermetabolic phenotype. When examining the respiratory exchange ratio (RER) among mdx mice, mdxLi+VWR (0.87) mice had a lower RER than mdx SED mice (0.91), indicative of enhanced fat oxidation. Glucose tolerance was equally impaired among mdx groups compared to WT mice. However, insulin tolerance was notably improved in mdx VWR and mdx Li+VWR mice, with a greater improvement observed in the mdx Li+VWR mice. CONCLUSION: Despite running less than mdx VWR mice, mdx Li+VWR mice had enhanced fatigue resistance, fat utilization, and insulin sensitivity, suggesting Li may be a viable treatment to improve muscle and metabolic function in mdx mice. CIHR CRC (Tier II) 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.

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