Abstract
Physical exercise is a robust lifestyle intervention. Among its many benefits, it is known for its enhancement of cognitive abilities. Nevertheless, the extent to which these benefits can be transmitted across generations (intergenerational inheritance to F1, and transgenerational to F2 and beyond) remains a topic of limited comprehension. We have already shown that cognitive improvements resulting from physical exercise can be inherited from parents to their offspring, proving intergenerational effects. So, we set out to explore whether these enhancements might extend transgenerationally, impacting the F2 generation. In this study, we initially examined the behavioral traits of second-generation (F2) male mice, whose grandfathers (F0) had an exercise intervention. Our findings revealed that F2 mice with physically active F0 grandparents displayed significantly improved memory recall, encompassing both spatial and non-spatial information when compared to their counterparts from sedentary F0 progenitors, and proving for the first time the transgenerational inheritance of physical exercise-induced cognitive enhancement. Surprisingly, while F2 memory improved (as in F1), adult hippocampal neurogenesis remained unchanged between experimental and control groups (unlike in F1). Additionally, our analysis of smallRNA sequences in hippocampus identified 35 differentially expressed miRNAs linked to important brain function categories. Notably, two of these miRNAs, miRNA-144 and miRNA-298, displayed robust negative correlation with cognitive performance. These findings highlight enduring transgenerational transmission of cognitive benefits associated with exercise, even after two generations. Furthermore, they suggest that moderate exercise training can have lasting positive effects, possibly orchestrated by a specific set of miRNAs that exert their influence across multiple generations.
Significance Statement Physical exercise is well known by its positive effects on body health and specifically on brain functioning and health. Here we test whether those effects are inherited from exercised grandparents to the second generation. We report here for the first time the transgenerational inheritance of moderate exercise-induced grandpaternal traits in grandson's cognition, even though some of the cellular changes induced in F1 vanish in F2, and suggesting that moderate exercise training has a longer-lasting effect than previously thought, most probably mediated by a small group of microRNAs acting across generations.
Footnotes
We are grateful to Laude Garmendia from the Animal House, at the Cajal Institute for her unpayable help and advice, to the Image Analysis Unit of the Cajal Institute. E.C. and P.M. were funded by a predoctoral fellowship (FPI) grant, and P.T. by a predoctoral fellowship (FPU). Work was supported by project grants H2020-INFRADEV-2016-2017 730879 (to LL.M.), and BFU2013-48907-R and BFU2016-77162-R (from Spanish Ministry of Economy and Competitiveness), and PID2019-110292RB-100 (from Spanish Ministry of Science and Innovation), (to J.L.T.).
All materials, data and associated protocols used in this work are available to interested readers. microRNAseq data are available uploaded at GEO accession GSE217487.
The authors declare that they have no conflict of interest.
Ethics Approval All experiments were performed according to the European Community Guidelines (Directive 2010/63/EU) and Spanish Guidelines (Royal Decree 53/2013) and related rules, and they were first validated by the Committee of Ethics and Animal Experimentation of the Cajal Institute (20/05/2016), subsequently favorably evaluated by the CSIC Ethics Committee (Subcommittee of Ethics) of the Spanish Research Council (07/27/2016) and eventually authorized by the competent authority, the Animal Protection Area of the Department of Environment of the Community of Madrid (10/26/2016 and 06/19/2020).
↵aBoth authors contributed equally to this paper
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