AUTHOR=Fernández-de la Torre Miguel , Fiuza-Luces Carmen , Valenzuela Pedro L. , Laine-Menéndez Sara , Arenas Joaquín , Martín Miguel A. , Turnbull Doug M. , Lucia Alejandro , Morán María 

TITLE=Exercise Training and Neurodegeneration in Mitochondrial Disorders: Insights From the Harlequin Mouse

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.594223

DOI=10.3389/fphys.2020.594223

ISSN=1664-042X

ABSTRACT=<sec><title>Aim</title><p>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, <italic>Hq</italic>) of AIF deficiency.</p></sec><sec><title>Methods</title><p>Male wild-type (WT) and <italic>Hq</italic> mice were assigned to an exercise (Ex) or control (sedentary [Sed]) group (<italic>n</italic> = 10–12/group). The intervention (aerobic and resistance exercises) was initiated upon the first symptoms of ataxia in <italic>Hq</italic> 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.</p></sec><sec><title>Results</title><p>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 (<italic>Hq</italic>-Sed), and 5.3 ± 0.1 months (<italic>Hq</italic>-Ex) (<italic>p</italic> = 0.489). A significant group effect was found for most variables indicating cerebellar dysfunction in <italic>Hq</italic> 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 (<italic>i.e.</italic>, no differences for <italic>Hq</italic>-Ex vs. <italic>Hq</italic>-Sed). On the contrary, in brain, the activity of complex V was higher in both <italic>Hq</italic> mice groups in comparison with WT animals (<italic>p</italic> &lt; 0.001), and <italic>post hoc</italic> analysis also revealed differences between sedentary and trained <italic>Hq</italic> mice.</p></sec><sec><title>Conclusion</title><p>A combined training program initiated when neurological symptoms and neuron death are already apparent is unlikely to promote neuroprotection in the cerebellum of <italic>Hq</italic> model of mitochondrial disorders, but it induces higher complex V activity in the brain.</p></sec>