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Advanced Neurology Voluntary running effects in PTEN knockout mouse

an increased expression of NR1, which could be related the effects of strategies such as physical exercise in both
to the fact that HT mice present neuronal hypertrophy females and males, given evidence of sex-dependent effects
and increased synapses in the cerebral cortex and in rodents and humans under physical exercise, as reviewed
hippocampus . This increase in NR1 expression by Rosenfeld . In addition, our previous observations
[19]
[86]
may be associated with the activation of excitatory indicated differences in basal levels of proteins, such as
synapses [78,79] . Ten days of running induced a reduction in PTEN, mTOR, and FoxO3a, between male and female
S6 phosphorylation, specifically in HT mice, possibly due mice . These differences may contribute to varying
[87]
to a combined effect of glutamatergic signaling activation susceptibilities to developing conditions such as autism
induced by running in other glutamate receptors such spectrum disorder [64,88] , potentially leading to distinct
as AMPA or metabotropic receptors and the activation responses to therapeutic treatments. Furthermore, while
of glutamatergic signaling induced by PTEN knocking literature has reported that a short protocol of voluntary
down itself (Figure 6E), leading to decreased S6 running causes morphological changes in synapses
[34]
phosphorylation in HT mice. and boosts neurogenesis , the present study’s short-
[31]
Other studies have shown similar results, including term running protocol did not fully counteract behavioral
the role of S6K1 in learning and memory [80-82] . In our deficits. Further studies are warranted to validate these
study, we observed that voluntary running decreased S6 findings.
phosphorylation (Figure 6A), suggesting a decreased activity/ Acknowledgments
expression of S6K. This effect could be a protective effect of
running, which reduces dysregulated cell growth, possibly We thank Larissa de Sá Lima for her technical assistance.
related to a downregulation of tumor suppressor expression/ We also thank Editage for the English editing service.
activity, such as PTEN. The pathway responsible for the
decrease in S6 phosphorylation induced by physical exercise Funding
appears to be independent of AKT and PTEN signaling, as This study was financially supported by Fundação de
we observed no differences among the groups regarding Amparo à Pesquisa do Estado de São Paulo to Elisa Mitiko
AKT expression and activity (Figures 6H and I). In addition, Kawamoto (FAPESP, grant number 2016/22996-9)
we observed that physical exercise caused a reduction and to Cristoforo Scavone (FAPESP grant number
in PTEN expression (Figure 6D), which could induce 2016/07427-8). Ana Maria Orellanais supported by the
S6 phosphorylation through the PIP3-PDK-P70S6K-S6 postdoc fellowship from Coordenação de Aperfeiçoamento
signaling pathway . Further investigation of other proteins de Pessoal de Nível Superior (CAPES). Natália Prudente de
[83]
related to S6K signaling is necessary to understand the Melloand Amanda Galvão Paixãowere supported by the
voluntary running induced decreased S6 phosphorylation in MSc fellowship from FAPESP. Elisa Mitiko Kawamoto
HT mice. and Cristoforo Scavone are research fellows of Conselho
Studies in the literature have demonstrated that Nacional de Desenvolvimento Científico e Tecnológico
10 weeks of running can increase PTEN expression in (CNPq).
the mouse skin tissue. This suggests that exercise may Conflict of interest
play a role in preventing skin cancer development [84] .
On the other hand, studies have shown that PTEN The authors declare no competing interests.
levels are increased in the synapses of the brains of
Alzheimer’s disease patients as the disease progresses, Author contributions
associated with synaptic failure [85] . These observations Conceptualization: Diana Zukas Andreotti, Cristoforo
suggest that both increased and decreased PTEN levels Scavone, Elisa Mitiko Kawamoto
could have varying effects on cell survival. In our study, Formal analysis: Diana Zukas Andreotti, Elisa Mitiko
we observed that exercise led to a reduction in PTEN Kawamoto
levels in the cerebral cortex of both WT and HT mice. Investigation: Diana Zukas Andreotti, Natália Prudente de
Further, analyses will be necessary to better understand Mello, Amanda Galvão Paixão, Ana Maria Orellana
the short-term running effects on PTEN expression in Writing – original draft: Diana Zukas Andreotti, Cristoforo
the brain. Scavone, Elisa Mitiko Kawamoto
Female PTEN-conditioned mice were used in the present
study, as female animals are rarely used in research due to Ethics approval and consent to participate
potential hormonal interference with data interpretation. All experimental procedures were approved by the
Therefore, it is essential to consider gender when evaluating Ethical Committee for Animal Research of the Institute of

Volume 2 Issue 3 (2023) 10 https://doi.org/10.36922/an.0872