Exercise training and neurodegeneration in mitochondrial disorders: Insights from the Harlequin mouse Articles uri icon

authors

  • FERNANDEZ DE LA TORRE, MIGUEL
  • FIUZA-LUCES, CARMEN
  • VALENZUELA, PEDRO L.
  • LAINE-MENENDEZ, SARA
  • ARENAS, JOAQUIN
  • TURNBULL, DOUG M.
  • LUCIA, ALEJANDRO
  • MORAN, MARIA

publication date

  • December 2020

start page

  • 1

end page

  • 15

volume

  • 11, 594223

International Standard Serial Number (ISSN)

  • 1664-042X

abstract

  • Aim: Cerebellar neurodegeneration is a main phenotypic manifestation of mitochondrial
    disorders caused by apoptosis-inducing factor (AIF) deficiency. We assessed the effects
    of an exercise training intervention at the cerebellum and brain level in a mouse model
    (Harlequin, Hq) of AIF deficiency.
    Methods: Male wild-type (WT) and Hq mice were assigned to an exercise (Ex) or
    control (sedentary [Sed]) group (n = 10–12/group). The intervention (aerobic and
    resistance exercises) was initiated upon the first symptoms of ataxia in Hq mice
    (∼3 months on average) and lasted 8 weeks. Histological and biochemical analyses of
    the cerebellum were performed at the end of the training program to assess indicators
    of mitochondrial deficiency, neuronal death, oxidative stress and neuroinflammation.
    In brain homogenates analysis of enzyme activities and levels of the oxidative
    phosphorylation system, oxidative stress and neuroinflammation were performed.
    Results: The mean age of the mice at the end of the intervention period did not
    differ between groups: 5.2 ± 0.2 (WT-Sed), 5.2 ± 0.1 (WT-Ex), 5.3 ± 0.1 (Hq-Sed),
    and 5.3 ± 0.1 months (Hq-Ex) (p = 0.489). A significant group effect was found for
    most variables indicating cerebellar dysfunction in Hq mice compared with WT mice
    irrespective of training status. However, exercise intervention did not counteract the
    negative effects of the disease at the cerebellum level (i.e., no differences for Hq-Ex vs.
    Hq-Sed). On the contrary, in brain, the activity of complex V was higher in both Hq mice
    groups in comparison with WT animals (p < 0.001), and post hoc analysis also revealed
    differences between sedentary and trained Hq mice.
    Conclusion: A combined training program initiated when neurological symptoms
    and neuron death are already apparent is unlikely to promote neuroprotection in the cerebellum of Hq model of mitochondrial disorders, but it induces higher complex V
    activity in the brain.

subjects

  • Biology and Biomedicine
  • Medicine

keywords

  • harlequin mouse; mitochondrial diseases; neurodegeneration; oxphos disorders; training