Exercise epigenetics is fueled by cell bioenergetics: Supporting role on brain plasticity and cognition.

Exercise has the unique aptitude to benefit overall health of body and brain. Evidence indicates that the effects of exercise can be saved in the epigenome for considerable time to elevate the threshold for various diseases. The action of exercise on epigenetic regulation seems central to building an "epigenetic memory" to influence long-term brain function and behavior. As an intrinsic bioenergetic process, exercise engages the function of the mitochondria and redox pathways to impinge upon molecular mechanisms that regulate synaptic plasticity and learning and memory. We discuss how the action of exercise uses mechanisms of bioenergetics to support a "epigenetic memory" with long-term implications for neural and behavioral plasticity. This information is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.

Aerobic exercise improves executive functions in females, but not males, without the BDNF Val66Met polymorphism.

BACKGROUND: Aerobic exercise promotes cognitive function in older adults; however, variability exists in the degree of benefit. The brain-derived neurotropic factor (BDNF) Val66Met polymorphism and biological sex are biological factors that have been proposed as important modifiers of exercise efficacy. Therefore, we assessed whether the effect of aerobic exercise on executive functions was dependent on the BDNFval66met genotype and biological sex. METHODS: We used data from a single-blind randomized controlled trial in older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Fifty-eight older adults were randomly assigned to either the 6 months, three times per week progressive aerobic training (AT) group or the usual care plus education control (CON) group. The secondary aim of the parent study included executive functions which were assessed with the Trail Making Test (B-A) and the Digit Symbol Substitution Test at baseline and trial completion at 6 months. RESULTS: Analysis of covariance, controlling for baseline global cognition and baseline executive functions performance (Trail Making Test or Digit Symbol Substitution Test), tested the three-way interaction between experimental group (AT, CON), BDNFval66met genotype (Val/Val carrier, Met carrier), and biological sex (female, male). Significant three-way interactions were found for the Trail Making Test (F(1,48) = 4.412, p < 0.04) and Digit Symbol Substitution Test (F(1,47) = 10.833, p < 0.002). Posthoc analyses showed female Val/Val carriers benefited the most from 6 months of AT compared with CON for Trail Making Test and Digit Symbol Substitution Test performance. Compared with CON, AT did not improve Trail Making Test performance in male Val/Val carriers or Digit Symbol Substitution Test performance in female Met carriers. CONCLUSIONS: These results suggest that future randomized controlled trials should take into consideration BDNF genotype and biological sex to better understand the beneficial effects of AT on cognitive function in vascular cognitive impairment to maximize the beneficial effects of exercise and help establish exercise as medicine for cognitive health.

Moderate exercise reveals the influence of ACTN3 R577X and ACE I/D polymorphisms on physical performance in non-athlete active subjects.

Genome variations contribute to the vast majority of interindividual differences and may decisively influence sports capability. This study was conceived as a means of finding out when exactly polymorphisms start being physically discriminative. The polymorphisms we studied were two of the best characterized ones: ACE I/D and ACTN3 R577X. These germline variants were determined in a cohort of 200 healthy volunteers from the university environment who underwent a series of physical evaluations that included a Cooper test, a 20-meter sprint test and a vertical jump test. Initially, no statistical association was found because the genetic effect was masked by those subjects with sedentary lifestyles. But when only physically active volunteers were considered, the ACE and ACTN3 genotypes were found to have an impact on heart rate after the Cooper test (p-value = 0.033 and 0.032 respectively) and ACTN3 was found to correlate with the total distance covered in the same test (p-value = 0.051). This can therefore be considered a paradigmatic example in which the environment might hide the genetic effect, with genotypic differences arising only upon training.

[Association analysis between genetic variants of matrix metalloproteinase enzyme 2 gene and the blood pressure of children and adolescents].

Objective: To explore the association between genetic variants of matrix metalloproteinase enzyme 2 (MMP2) gene and the blood pressure of children and adolescents. Methods: This cross-sectional study was performed in 2016 and included 4 155 children and adolescents in the urban area of Guangzhou. Physical examinations (including body height, weight, and blood pressure), questionnaires (including general characteristics, physical exercise, parental educational level, household income, etc.), and blood sampling were performed. Multivariable linear regression models were used to investigate the associations of MMP2 genetic variations (rs243865, rs7201) and the genetic risk score (GRS) level with standardized blood pressure. Mediating effect of standardized body mass index (BMI) was further assessed by process analysis in the association between GRS level and blood pressure, and potential additive interaction between physical activity and GRS level was analyzed using the product term in the regression model. Results: A total of 4 155 primary and secondary schoolchildren were finally included in the analysis, consisting of 1 401 (33.7%) second grade pupils of primary school, 1 422 (34.2%) first grade pupils of middle school, and 1 332 (32.1%) first-grade students of senior high school. After adjusting for age, sex, parental educational level, and family income, as compared to the rs243865 TT genotype, the CC/CT genotype increased diastolic blood pressure (DBP) by 0.461 standard deviations (SD) (ß for dominant model=0.461, 95%CI 0.199-0.723). When compared to the rs7201 CC genotype, the AA/AC genotype showed 0.147 SD higher systolic blood pressure (SBP) (ß for recessive model=0.147, 95%CI 0.014-0.279) and 0.171 SD increased DBP (ß for recessive model=0.171, 95%CI 0.039-0.304). For each increment of GRS level, SBP and DBP increased by 0.151 SD (ß for dominant model=0.151, 95%CI 0.029-0.272) and 0.242 SD (ß=0.242, 95%CI 0.120-0.363), respectively. The mediating effect of BMI accounted for 28.3% and 12.6% of the total effect of GRS on SBP and DBP, respectively. After controlling BMI, the direct effect of GRS on DBP remained statistically significant (P<0.001). The insufficient moderate-to-vigorous physical activity (<0.5 h/d) showed a significant interaction with GRS on SBP under additive scale (ß for interaction=0.518, 95%CI 0.088-0.949, P=0.018). Conclusions: rs243865 and rs7201 variants in MMP2 gene are associated with the elevated blood pressure of children and adolescents. Obesity may yield a mediation role in the associations, while insufficient physical activity may have a positively additive interaction with MMP2 genetic variants.

Untargeted sequencing of circulating microRNAs in a healthy and diseased older population.

We performed untargeted profiling of circulating microRNAs (miRNAs) in a well characterized cohort of older adults to verify associations of health and disease-related biomarkers with systemic miRNA expression. Differential expression analysis revealed 30 miRNAs that significantly differed between healthy active, healthy sedentary and sedentary cardiovascular risk patients. Increased expression of miRNAs miR-193b-5p, miR-122-5p, miR-885-3p, miR-193a-5p, miR-34a-5p, miR-505-3p, miR-194-5p, miR-27b-3p, miR-885-5p, miR-23b-5b, miR-365a-3p, miR-365b-3p, miR-22-5p was associated with a higher metabolic risk profile, unfavourable macro- and microvascular health, lower physical activity (PA) as well as cardiorespiratory fitness (CRF) levels. Increased expression of miR-342-3p, miR-1-3p, miR-92b-5p, miR-454-3p, miR-190a-5p and miR-375-3p was associated with a lower metabolic risk profile, favourable macro- and microvascular health as well as higher PA and CRF. Of note, the first two principal components explained as much as 20% and 11% of the data variance. miRNAs and their potential target genes appear to mediate disease- and health-related physiological and pathophysiological adaptations that need to be validated and supported by further downstream analysis in future studies.Clinical Trial Registration: ClinicalTrials.gov: NCT02796976 ( https://clinicaltrials.gov/ct2/show/NCT02796976 ).

The Impact of Exercise on Telomere Length, DNA Methylation and Metabolic Footprints.

Aging as a major risk factor influences the probability of developing cancer, cardiovascular disease and diabetes, amongst others. The underlying mechanisms of disease are still not fully understood, but research suggests that delaying the aging process could ameliorate these pathologies. A key biological process in aging is cellular senescence which is associated with several stressors such as telomere shortening or enhanced DNA methylation. Telomere length as well as DNA methylation levels can be used as biological age predictors which are able to detect excessive acceleration or deceleration of aging. Analytical methods examining aging are often not suitable, expensive, time-consuming or require a high level of technical expertise. Therefore, research focusses on combining analytical methods which have the potential to simultaneously analyse epigenetic, genomic as well as metabolic changes.

The genetics of human performance.

Human physiology is likely to have been selected for endurance physical activity. However, modern humans have become largely sedentary, with physical activity becoming a leisure-time pursuit for most. Whereas inactivity is a strong risk factor for disease, regular physical activity reduces the risk of chronic disease and mortality. Although substantial epidemiological evidence supports the beneficial effects of exercise, comparatively little is known about the molecular mechanisms through which these effects operate. Genetic and genomic analyses have identified genetic variation associated with human performance and, together with recent proteomic, metabolomic and multi-omic analyses, are beginning to elucidate the molecular genetic mechanisms underlying the beneficial effects of physical activity on human health.

Polygenic Score for Physical Activity Is Associated with Multiple Common Diseases.

INTRODUCTION: Genetic pleiotropy, in which the same genes affect two or more traits, may partially explain the frequently observed associations between high physical activity (PA) and later reduced morbidity or mortality. This study investigated associations between PA polygenic risk scores (PRS) and cardiometabolic diseases among the Finnish population. METHODS: PRS for device-measured overall PA were adapted to a FinnGen study cohort of 218,792 individuals with genomewide genotyping and extensive digital longitudinal health register data. Associations between PA PRS and body mass index, diseases, and mortality were analyzed with linear and logistic regression models. RESULTS: A high PA PRS predicted a lower body mass index (ß = -0.025 kg·m-2 per one SD change in PA PRS, SE = 0.013, P = 1.87 × 10-80). The PA PRS also predicted a lower risk for diseases that typically develop later in life or not at all among highly active individuals. A lower disease risk was systematically observed for cardiovascular diseases (odds ratio [OR] per 1 SD change in PA PRS = 0.95, P = 9.5 × 10-19) and, for example, hypertension [OR = 0.93, P = 2.7 × 10-44), type 2 diabetes (OR = 0.91, P = 4.1 × 10-42), and coronary heart disease (OR = 0.95, P = 1.2 × 10-9). Participants with high PA PRS had also lower mortality risk (OR = 0.97, P = 0.0003). CONCLUSIONS: Genetically less active persons are at a higher risk of developing cardiometabolic diseases, which may partly explain the previously observed associations between low PA and higher disease and mortality risk. The same inherited physical fitness and metabolism-related mechanisms may be associated both with PA levels and with cardiometabolic disease risk.

TGF-ß Induction of miR-143/145 Is Associated to Exercise Response by Influencing Differentiation and Insulin Signaling Molecules in Human Skeletal Muscle.

Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-ß, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-ß-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-ß1-treated human skeletal muscle cells corroborated the effects of TGF-ß1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-ß1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-ß1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-ß signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-ß1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-ß signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-ß and finetuned IRS1 suppression by miR-143-3p.

Unlocking the Role of Exercise on CD4+ T Cell Plasticity.

A hallmark of T cell ageing is a loss of effector plasticity. Exercise delays T cell ageing, yet the mechanisms driving the effects of exercise on T cell biology are not well elucidated. T cell plasticity is closely linked with metabolism, and consequently sensitive to metabolic changes induced by exercise. Mitochondrial function is essential for providing the intermediate metabolites necessary to generate and modify epigenetic marks in the nucleus, thus metabolic activity and epigenetic mechanisms are intertwined. In this perspective we propose a role for exercise in CD4+ T cell plasticity, exploring links between exercise, metabolism and epigenetic reprogramming.

Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports.

Recently, several studies have highlighted the tight connection between mitochondria and physical activity. Mitochondrial functions are important in high-demanding metabolic activities, such as endurance sports. Moreover, regular training positively affects metabolic health by increasing mitochondrial oxidative capacity and regulating glucose metabolism. Exercise could have multiple effects, also on the mitochondrial DNA (mtDNA) and vice versa; some studies have investigated how mtDNA polymorphisms can affect the performance of general athletes and mtDNA haplogroups seem to be related to the performance of elite endurance athletes. Along with several stimuli, including pathogens, stress, trauma, and reactive oxygen species, acute and intense exercise also seem to be responsible for mtDNA release into the cytoplasm and extracellular space, leading to the activation of the innate immune response. In addition, several sports are characterized by a higher frequency of injuries, including cranial trauma, associated with neurological consequences. However, with regular exercise, circulating cell-free mtDNA levels are kept low, perhaps promoting cf-mtDNA removal, acting as a protective factor against inflammation.

Epigenetic Regulation of Inflammatory Responses in the Context of Physical Activity.

Epigenetic modifications occur in response to environmental changes and play a fundamental role in the regulation of gene expression. PA is found to elicit an inflammatory response, both from the innate and adaptive divisions of the immunological system. The inflammatory reaction is considered a vital trigger of epigenetic changes that in turn modulate inflammatory actions. The tissue responses to PA involve local and general changes. The epigenetic mechanisms involved include: DNA methylation, histone proteins modification and microRNA. All of them affect genetic expression in an inflammatory milieu in physical exercise depending on the magnitude of physiological stress experienced by the exerciser. PA may evoke acute or chronic biochemical and physiological responses and have a positive or negative immunomodulatory effect.

The effect of dietary total antioxidant capacity (DTAC) and Caveolin-1 gene variant interaction on cardiovascular risk factors among overweight and obese women: A cross-sectional investigation.

BACKGROUND: Previous studies have shown that the Caveolin-1 (CAV-1) gene variant may be associated with Cardiovascular disease (CVD) risk. Moreover, dietary total antioxidant capacity (DTAC) has been shown to potentially elicit favorable effects on CVD risk. Therefore, this study sought to investigate the effect of DTAC and CAV-1 interaction on CVD risk factors. METHODS: This cross-sectional study consisted of 352 women, with overweight and/or obesity, aged 18-48years from Iran. A food frequency questionnaire (FFQ), with 147 items, was used to assess dietary intake. The CAV-1 rs 3807992 and anthropometric data were measured by the PCR-RFLP method and bioelectrical impedance analysis (BIA), respectively. Serum profiles were measured by standard protocols. Participants were also divided into two groups based on DTAC score and rs3807992 genotype. RESULTS: The mean age of the participants was 37.34 ± 9.11 and 36.01 ± 9.12 years for homozygous (GG) and minor allele carriers (AG + AA) respectively.The mean ± SD of insulin, total cholesterol (TC),high-density lipoprotein (HDL), low-density lipoprotein (LDL) and TG of participants were 1.21 ± 0.23, 185.3 ± 35.77, 46.58 ± 10.86, 95.3 ± 24.12 and 118.1 ± 58.88, respectively. There was a significant difference between genotypes for physical activity (P = 0.05), HDL (P < 0.001), insulin (P = 0.04), CRI-I (TC/HDL-C) (P = 0.01), and CRI-II (LDL-C/HDL-C) (P = 0.04). Our findings also showed, after controlling for confounding factors, significant interactions between DTAC score and the A allele carrier group on TC (Pinteraction = 0.001), LDL (Pinteraction = 0.001), insulin (Pinteraction = 0.08), HOMA-IR (Pinteraction = 0.03), AC ((TC - HDL - C)/HDL - C) (Pinteraction = 0.001), and CHOLINDEX (LDL-C-HDL-C) (Pinteraction = 0.02). CONCLUSION: The results of the present study indicate that high DTAC intake may modify the odds of risk factors for CVD in AA and AG genotypes of rs 3807992. These results highlight that diet, gene variants, and their interaction, should be considered in CVD risk assessment.

Co-expression analysis identifies networks of miRNAs implicated in biological ageing and modulated by short-term interval training.

Exercise training seems to promote healthy biological ageing partly by inducing telomere maintenance, yet the molecular mechanisms are not fully understood. Recent studies have emphasised the importance of microRNAs (miRNAs) in ageing and their ability to mirror pathophysiological alterations associated with age-related diseases. We examined the association between aerobic fitness and leukocyte telomere length before determining the influence of vigorous exercise training on the regulation of leukocyte miRNA networks. Telomere length was positively correlated to aerobic fitness (r = 0.32, p = 0.02). 104 miRNAs were differentially expressed after six weeks of thrice-weekly sprint interval training (SIT) in healthy men (q < 0.05). Gene co-expression analysis (WGCNA) detected biologically meaningful miRNA networks, five of which were significantly correlated with pre-SIT and post-SIT expression profiles (p < 0.001) and telomere length. Enrichment analysis revealed that the immune response, T cell differentiation and lipid metabolism associated miRNAs clusters were significantly down-regulated after SIT. Using data acquired from the Gene Expression Omnibus (GEO), we also identified two co-expressed miRNAs families that were modulated by exercise training in previous investigations. Collectively, our findings highlight the miRNA networks implicated in exercise adaptations and telomere regulation, and suggest that SIT may attenuate biological ageing through the control of the let-7 and miR-320 miRNA families.

FABP2 Ala54Thr Polymorphism and Post-Training Changes of Body Composition and Biochemical Parameters in Caucasian Women.

The functional FABP2 Ala54Thr polymorphism (rs1799883) is strongly associated with lipid and carbohydrate metabolism, although the function of its potential modifying effect on training-induced changes in obesity-related parameters is still unknown. The aim of the present study was to investigate the influence of the Ala54Thr polymorphism on post-training changes of selected body mass and body composition measurements, as well as with biochemical parameters of energy metabolism. Accordingly, alleles and genotypes distribution in a group of 168 young, nonobese Caucasian women measured for chosen body composition parameters, lipid profile, and glucose levels before and after the completion of a 12-week aerobic training program were studied. Although the obtained results showed changes in body mass, BMI, FM, %FM, FFM, TBW, HDL-C, and glucose levels during the training program, none of the examined parameters changed significantly across the FABP2 genotypes. Instead, we found a main effect of genotype on BMI (p = 0.033), with carriers of the Thr54 allele having a higher BMI during the whole study period compared with the Ala54 carriers. We confirm that the FABP2 Ala54Thr polymorphism may help identify women at risk for overweight and obesity. However, we did not notice evidence of an interaction between physical activity and the Ala54Thr polymorphism on the examined parameters.

Physical exercise, obesity, inflammation and neutrophil extracellular traps (NETs): a review with bioinformatics analysis.

Neutrophil extracellular traps (NETs) represent an innate organism defense mechanism characterized by neutrophil release of intracellular material to capture any aggressor agent. Elevated NETs release is associated with increased inflammatory response and related diseases, such as obesity. Chronic physical training is one of the main strategies to treat and prevent obesity. The relationship between physical training and NETs is still under study. The present review, followed by a bioinformatics analysis, demonstrates the meaningful connection between physical exercise, obesity, and NETs. The bioinformatics indicated TNF-α as a leading gene after the ontological analysis followed by positive-interleukin-6 regulation, chemokines, and inflammatory response regulation. The main results pointed to a relevant regulatory effect of physical training on NETs release, indicating physical exercise as a possible therapeutic target on modulating NETs and inflammation.

Physical activity, sedentary behavior and risk of coronary artery disease, myocardial infarction and ischemic stroke: a two-sample Mendelian randomization study.

AIMS: Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. METHODS AND RESULTS: We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. CONCLUSIONS: These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased.

GWAS reveal a role for the central nervous system in regulating weight and weight change in response to exercise.

Body size and weight show considerable variation both within and between species. This variation is controlled in part by genetics, but also strongly influenced by environmental factors including diet and the level of activity experienced by the individual. Due to the increasing obesity epidemic in much of the world, there is considerable interest in the genetic factors that control body weight and how weight changes in response to exercise treatments. Here, we address this question in the Drosophila model system, utilizing 38 strains of the Drosophila Genetics Reference Panel. We use GWAS to identify the molecular pathways that control weight and weight changes in response to exercise. We find that there is a complex set of molecular pathways controlling weight, with many genes linked to the central nervous system (CNS). The CNS also plays a role in the weight change with exercise, in particular, signaling from the CNS. Additional analyses revealed that weight in Drosophila is driven by two factors, animal size, and body composition, as the amount of fat mass versus lean mass impacts the density. Thus, while the CNS appears to be important for weight and exercise-induced weight change, signaling pathways are particularly important for determining how exercise impacts weight.

Evaluation of the usefulness of saliva for mosaic loss of chromosome Y analysis.

Mosaic loss of chromosome Y (mLOY) in leukocytes has attracted much attention as an emerging biomarker of aging and aging-related diseases. We evaluated the usefulness of saliva for mLOY analysis and showed that saliva-derived mLOY is significantly associated with aging and increased physical activity, but not with smoking. While these data support the robust association between saliva-derived mLOY and aging, caution is required when comparing data from saliva-derived and blood-derived mLOY.

Building-up fit muscles for the future: Transgenerational programming of skeletal muscle through physical exercise.

'Special issue - In Utero and Early Life Programming of Aging and Disease'. Skeletal muscle (SM) adaptations to physical exercise (PE) have been extensively studied due, not only to the relevance of its in situ plasticity, but also to the SM endocrine-like effects in noncontractile tissues, such as brain, liver or adipocytes. Regular PE has been considered a pleiotropic nonpharmacological strategy to prevent and counteract the deleterious consequences of several metabolic, cardiovascular, oncological and neurodegenerative disorders. Additionally, PE performed by parents seems to have a direct impact in the offspring through the transgenerational programming of different tissues, such as SM. In fact, SM offspring programming mechanisms seems to be orchestrated, at least in part, by epigenetic machinery conditioning transcriptional or post-transcriptional processes. Ultimately, PE performed in the early in life is also a critical window of opportunity to positively modulate the juvenile and adult phenotype. Parental PE has a positive impact in several health-related offspring outcomes, such as SM metabolism, differentiation, morphology and ultimately in offspring exercise volition and endurance. Also, early-life PE counteracts conceptional-related adverse effects and induces long-lasting healthy benefits throughout adulthood. Additionally, epigenetics mechanisms seem to play a key role in the PE-induced SM adaptations. Despite the undoubtedly positive role of parental and early-life PE on SM phenotype, a strong research effort is still needed to better understand the mechanisms that positively regulate PE-induced SM programming.