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Voluntary wheel running: patterns and physiological effects in mice.

ABSTRACT: Exercise can prevent and improve the pathophysiology of diseases and promote healthy aging. Thus, understanding the mechanisms that regulate the beneficial effects of exercise may lead to the development of new strategies to enhance quality of life and to counteract chronic diseases. Voluntary wheel running is an interesting model to study the effects of exercise in mice. Compared to forced treadmill exercise, voluntary wheel running presents several advantages such as: 1) running pattern is similar to natural running behavior of mice; 2) it is performed under non-stressed conditions, according to the rhythmicity of the animal; 3) it does not require direct interference from the researcher, and can be easily applied in long-term studies. Mice run spontaneously when given access to running wheels, for a total distance of ?4 to 20 km per day and a total activity time of ?3 to 7 hours a day. Hence, voluntary wheel running can result in robust endurance-like adaptation in skeletal and cardiac muscles and protect from sarcopenia. However, due to the lack of control over exercise parameters in voluntary exercise models, it is important for the researcher to understand the patterns and variability of wheel running in mice, as well as the factors that can affect voluntary running activity. Overall, voluntary wheel running in mice is a very interesting approach to study the chronic adaptation to exercise, analyze the effects of exercise, and test exercise capacity in different experimental models.

SUBMITTER: Manzanares G

PROVIDER: S-EPMC6301263 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Voluntary wheel running: patterns and physiological effects in mice.

Manzanares G G Brito-da-Silva G G Gandra P G PG

Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 20181210 1

Exercise can prevent and improve the pathophysiology of diseases and promote healthy aging. Thus, understanding the mechanisms that regulate the beneficial effects of exercise may lead to the development of new strategies to enhance quality of life and to counteract chronic diseases. Voluntary wheel running is an interesting model to study the effects of exercise in mice. Compared to forced treadmill exercise, voluntary wheel running presents several advantages such as: 1) running pattern is sim ...[more]

PMID: 30539969

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Project description:Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: -9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: -29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.

Project description:We tested the hypothesis that voluntary wheel running would complement microdystrophin gene therapy to improve muscle function in young mdx mice, a model of Duchenne muscular dystrophy. mdx mice injected with a single dose of AAV9-CK8-microdystrophin or vehicle at age 7 weeks were assigned to three groups: mdxRGT (run, gene therapy), mdxGT (no run, gene therapy), or mdx (no run, no gene therapy). Wild-type (WT) mice were assigned to WTR (run) and WT (no run) groups. WTR and mdxRGT performed voluntary wheel running for 21 weeks; remaining groups were cage active. Robust expression of microdystrophin occurred in heart and limb muscles of treated mice. mdxRGT versus mdxGT mice showed increased microdystrophin in quadriceps but decreased levels in diaphragm. mdx final treadmill fatigue time was depressed compared to all groups, improved in mdxGT, and highest in mdxRGT. Both weekly running distance (km) and final treadmill fatigue time for mdxRGT and WTR were similar. Remarkably, mdxRGT diaphragm power was only rescued to 60% of WT, suggesting a negative impact of running. However, potential changes in fiber type distribution in mdxRGT diaphragms could indicate an adaptation to trade power for endurance. Post-treatment in vivo maximal plantar flexor torque relative to baseline values was greater for mdxGT and mdxRGT versus all other groups. Mitochondrial respiration rates from red quadriceps fibers were significantly improved in mdxGT animals, but the greatest bioenergetic benefit was observed in the mdxRGT group. Additional assessments revealed partial to full functional restoration in mdxGT and mdxRGT muscles relative to WT. These data demonstrate that voluntary wheel running combined with microdystrophin gene therapy in young mdx mice improved whole-body performance, affected muscle function differentially, mitigated energetic deficits, but also revealed some detrimental effects of exercise. With microdystrophin gene therapy currently in clinical trials, these data may help us understand the potential impact of exercise in treated patients.

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Voluntary wheel running: patterns and physiological effects in mice.

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Voluntary wheel running: patterns and physiological effects in mice.

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