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Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice

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  • Thomas H. Lee

    (Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong
    These authors contributed equally to this work.
    Current address: Neurocentre Magendie, INSERM U1215, University of Bordeaux, 33000 Bordeaux, France.)

  • Malegaddi Devaki

    (Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong
    These authors contributed equally to this work.)

  • Douglas A. Formolo

    (Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong)

  • Julia M. Rosa

    (Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong)

  • Andy S. K. Cheng

    (Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong)

  • Suk-Yu Yau

    (Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
    Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong)

Abstract

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.

Suggested Citation

  • Thomas H. Lee & Malegaddi Devaki & Douglas A. Formolo & Julia M. Rosa & Andy S. K. Cheng & Suk-Yu Yau, 2023. "Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice," IJERPH, MDPI, vol. 20(7), pages 1-17, April.
  • Handle: RePEc:gam:jijerp:v:20:y:2023:i:7:p:5371-:d:1114779
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    References listed on IDEAS

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    1. Christoph Anacker & Victor M. Luna & Gregory S. Stevens & Amira Millette & Ryan Shores & Jessica C. Jimenez & Briana Chen & René Hen, 2018. "Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus," Nature, Nature, vol. 559(7712), pages 98-102, July.
    2. Kay M. Tye & Julie J. Mirzabekov & Melissa R. Warden & Emily A. Ferenczi & Hsing-Chen Tsai & Joel Finkelstein & Sung-Yon Kim & Avishek Adhikari & Kimberly R. Thompson & Aaron S. Andalman & Lisa A. Gun, 2013. "Dopamine neurons modulate neural encoding and expression of depression-related behaviour," Nature, Nature, vol. 493(7433), pages 537-541, January.
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