Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline.

José Maria Costa-Júnior,Gustavo J Santos,Diana L Bernstein,Everardo M Carneiro,Ricardo Freitas-Dias,Elena G Ruano,Vasumathi Kameswaran,Sandra Mara Ferreira,Claudio C Zoppi,Camila A M De Oliveira,Mirian Ayumi Kurauti,Klaus H Kaestner,Jonathan Schug,Antonio C Boschero

doi:10.3390/ijms23010001

Abstract

Background/Aims: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease’s (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. Methods: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. Results: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. Conclusion: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

Highlights

The dramatic increase in the incidence of Type 2 diabetes over the past several decades supports the overriding influence of lifestyle changes rather than alterations in our genetic makeup on disease progression [1–5]
To determine the molecular underpinnings of the transgenerational effect of paternal exercise training on glucose homeostasis and insulin sensitivity in the offspring, we focused on DNA methylation analysis, an epigenetic marker
To assess whether the DNA methylation changes we discovered in the skeletal muscle of the offspring of exercise-trained fathers were epigenetically inherited, we evaluated the methylation profile of the sperm of

Summary

Introduction

The dramatic increase in the incidence of Type 2 diabetes over the past several decades supports the overriding influence of lifestyle changes rather than alterations in our genetic makeup on disease progression [1–5]. Many individuals presenting with metabolic diseases such as obesity or diabetes benefit from changes in lifestyle such as increased physical activity and/or diminished caloric intake [2,6–8]. An imbalance in energy intake, whether sub-nutrition or over-nutrition, in the parental generation has been linked to the development of metabolic disease in human, drosophila, and rodent offspring [11–14], which, in turn, increases the risk for the development of cancer, endocrine disruption, and other metabolic complications [3,15–17]. This phenomenon was observed first by Barker, who established the ‘developmental origin for health and disease’ (DOHAD) hypothesis [16,18,19]. While many studies have confirmed the developmental origins of diseases [11,17,20,21], the molecular mediators that transmit parental phenotypes to the generation are largely unknown

Methods

Results

Conclusion