Influence of Maternal Exercise on Maternal and Offspring Metabolic Outcomes

Abstract

Epigenetic transmission of metabolic disease to an offspring increases their risk for development of metabolic disease later in life. With the increasing rates of obesity in women of child-bearing age it is critical to develop strategies to prevent perpetuating metabolic disease across generations. Maternal exercise during gestation imprints offspring metabolic phenotype, thus increasing their imperviousness to metabolic assaults later in life. In rodent models, maternal exercise before and during gestation leads to enhanced offspring glycemic control, mitochondrial bioenergetics, and lower adiposity, which decreases their risk for development of future metabolic disease. In humans, maternal gestational exercise decreases pregnancy complications and improves maternal and offspring metabolism on both the whole-body and the cellular level. Maternal exercise restores the obesity-induced metabolic derangements, restoring maternal and offspring metabolic phenotype. While unknown, different exercise modalities might have a differential effect, however, evidence remains scarce.

1. Introduction

Rates of pediatric obesity are escalating worldwide. Increasing rates of childhood obesity are likely to translate into a high cumulative incidence of metabolic disease (i.e., type 2 diabetes mellitus (T2D)) and further exacerbate the strain on the healthcare system, public health, and global economy [1]. The development of obesity is often attributed to a combination of genetic and acquired environmental factors. It is well established that the epigenetic transmission of metabolic diseases to offspring will increase their risk for the development of metabolic disorders later in life [2]. Accordingly, environmental exposures (i.e., overnutrition) experienced by parents during intrauterine and early postnatal life will have profound effects on offspring health. Because of the increasing rates of obesity among individuals of child-bearing age, it is critical to develop strategies to prevent the transgenerational propagation of metabolic disease.

It is widely understood that physical activity induces an array of positive metabolic changes that can delay and/or reverse the deleterious effects of obesity. While the mechanisms of action behind the benefits of regular physical exercise are well-documented, research has mostly focused on the person performing the exercise. Consequently, there is limited understanding in the mechanisms by which regular maternal exercise influences the metabolic phenotype of offspring. Further, while studies regarding the effects of maternal exercise on pregnancy, maternal, and offspring outcomes are available and reviewed [3, 4, 5, 6, 7, 8], data which characterizes the mediating factors affecting offspring developmental programming is limited [9]. This is partly due to limitations in revealing the cellular and molecular mechanisms behind maternal exercise-derived benefits that stem from the inability to obtain neonate tissue samples (i.e., skeletal muscle (SkM)).

An understanding of the explicit alterations that maternal exercise causes in the offspring phenotype would allow for the characterization of novel targets and could be used to render different therapeutics for metabolic diseases. Further, elucidating the specific biological mechanisms induced by different exercise modalities could permit this lifestyle intervention to serve analogous to a targeted therapy. Thus, there is potential for different exercise modalities to be used in a prescription-like manner to generate a unique set of metabolic adaptations suitable for treating and/or reducing offspring predispositions to metabolic disease. In view of this possibility, the focus of this chapter will be on describing the mechanisms behind the effects of the maternal exercise on offspring metabolic programing. Emphasis will be on the analysis of the biological mechanisms behind specific metabolic adaptations that promote imperviousness to metabolic challenges (i.e., overnutrition) leading to obesity and T2D. Further, considering that mitochondrial dysfunction and insulin resistance (IR) are major constituents of these metabolic diseases, a focus will be on the alterations in offspring mitochondrial bioenergetics and glycemic control.

2. Learning from rodent models

2.1 Maternal obesity and offspring health

The use of rodent models has allowed researchers to study how various environmental factors during critical windows of prenatal and early postnatal development alter metabolic phenotype and elicit tissue specific adaptations in progeny. Considering the ever-increasing rates of obesity, dietary habits, particularly overnutrition, during gestation have a critical role in fetal development and are often the focus of investigations. Maternal obesity and often concomitant IR increase the propensity of the development and transmission of metabolic disease onto progeny. A maternal obesogenic diet during fetal life readily programs first and second generation offspring into a T2D-like phenotype, even without additional dietary insults (i.e., overnutrition) administered to these generations [10].

Maternal obesity elicits multifaceted effects on offspring behavioral habits and physiology. Offspring from obese mothers have a tendency to be physically inactive and hyperphagic [11, 12]. Further, offspring adopt a metabolic syndrome-like phenotype with impaired glucose tolerance, higher blood triglycerides, cholesterol, and leptin, but lower adiponectin levels, which increases offspring predisposition for the development of cardiometabolic disease later in life [11, 12]. Maternal obesogenic diet consumption during gestation increases offspring adiposity primarily through adipocyte hypertrophy [12, 13, 14]. Adipocyte hypertrophy, rather than hyperplasia, is associated with lower insulin responsiveness, inflammation, and an overall dysregulation of systemic energy metabolism [15]. Increased adiposity is further accompanied by a greater intramuscular fat accretion associated with higher PPARγ mRNA expression which could contribute to the development of lipotoxicity-induced SkM IR observed in these offspring [13]. Offspring from obese mothers have a restricted SkM growth potential which subsequently decreases their SkM cross-sectional area [13]. These alterations combined with lower GLUT4 and insulin receptor mRNA expression, as observed in SkM of offspring from obese mothers, attenuates their potential for insulin-stimulated glucose uptake and increase the propensity of offspring to develop hyperglycemia [13]. Considering that SkM is responsible for the majority of postprandial glucose uptake, these alterations have a profound effect on glucose homeostasis and could increase the risk for the development of T2D. Finally, maternal overnutrition leads to the downregulation of pathways associated with mitochondrial oxidation and lowers mitochondrial electron transport protein expression, leading to mitochondrial dysfunction [14].

Together, these alterations can lead to derangements in energy metabolism later in offspring life and increase their proclivity for metabolic disease. In view of this, it is essential to explore the effects of different lifestyle interventions that can alleviate the detrimental effects of maternal obesity on offspring metabolic dysregulation. Regular exercise is known to be protective against metabolic derangements observed in obesity and T2D in mother and offspring. Accordingly, illumination of the effects of maternal exercise on offspring body composition, glycemic control, and mitochondrial functioning will underline mechanistic alterations behind enhanced metabolic phenotype.

2.2 Maternal exercise enhances offspring metabolic phenotype

2.2.1 Body composition

While most studies support the notion that exercise before and during gestation has an effect on offspring body weight (BW), findings are inconsistent [9]. Reports remain divided between maternal exercise causing a decrease [16, 17, 18, 19, 20], increase [21, 22], or having no effect on litter [23, 24, 25] or pup BW [26, 27, 28, 29, 30]. Additionally, these studies remain divided between maternal exercise leading to less weight gain with aging in offspring or having no effect on age-related weight gain. For example, Quiclet and associates found no effect of maternal exercise on male offspring BW at weaning or at 7 months of age; however, in their subsequent study, a decrease in BW was observed at weaning and 3 months of age, despite using the same animal and exercise model [17, 28]. Similarly, despite the use of the same animal species and exercising method across studies, change in BW is inconsistent in male offspring from exercising mothers at ~12 months of age [29, 30]. In addition to BW, discrepancies regarding the effect of maternal exercise on body composition have been observed across studies and offspring gender [16, 17, 18, 21, 23, 24, 25, 27, 28, 29, 31]. Carter et al. [26] reported an increase in lean mass and subsequent decrease in fat mass in males ~12 months of age; however, this was not observed in female offspring. Conversely, lower body fat percentages in female offspring have been shown in other studies [16, 19, 31]. Nonetheless, it is worth noting that body composition changes seem to be more prominent in male offspring. This is potentially because of a tendency for greater weight gain with aging; however, the exact reason for the sex-specific differences remains unknown [9].

With consideration of these inconsistencies, it is difficult to determine if offspring BW is a causal factor or is determined by alterations in the metabolic phenotype of the offspring. Interestingly, it has been observed that the alterations in BW, lean and fat mass are secondary to other metabolic improvements and often develop later in offspring life. For instance, improvements in glucose metabolism have been observed in multiple studies regardless of inconsistencies in BW and body composition changes between studies [16, 26, 29, 31]. This suggests that metabolic reprograming is, at least in part, independent of body composition changes and is more likely causal of these alterations with aging or subsequent metabolic challenges (i.e., overnutrition). Accordingly, significantly smaller BW and fat mass gains were observed in sedentary pups from exercised mothers who were fed a high-fat-high-sugar diet (HFHS) compared to HFHS-diet fed pups from non-exercising mothers [17, 20]. This suggests that subsequent nutritional manipulations in offspring may be needed to elicit changes in BW and body composition and to better understand the relationship between changes in BW and metabolic reprogramming.

2.2.2 Glucose tolerance

Since SkM and liver metabolic alterations have a profound impact on the development of systemic metabolic disease, it is important to address how maternal exercise alters metabolism of these tissues. Exercise prior to and during pregnancy increases glucose tolerance and insulin sensitivity across offspring lifespan independent of changes in BW [16, 17, 19, 26, 27, 30, 31] and persist in second generation progeny [32]. Interestingly, in offspring from metabolically healthy exercising mothers, improvements in glucose tolerance are mostly observed in adulthood of the animal rather than early stages of life (i.e., at weaning) [16, 18, 25, 26]. This might be the case considering that the effects of maternal exercise are “diluted” in offspring from metabolically healthy mothers, and therefore these effects might be more pronounced in offspring from mothers with obesity, considering the previously described metabolic derangements that maternal obesity elicits. Accordingly, offspring and maternal glucose intolerance stemming from maternal obesity can be rescued by maternal pregestational and gestation exercise, and this effect is evident in early offspring life [18, 25, 29, 30, 31, 33]. These findings suggest that maternal exercise could enhance the ability of offspring to resist the future development of IR; however, these improvements may not be readily observed in healthy offspring before adulthood or without a subsequent metabolic challenge.

Multiple in vivo and in vitro techniques have been used in studies to confirm that enhanced glucose disposal stems from improved offspring peripheral (i.e., SkM) insulin sensitivity as a result of maternal exercise. Improved insulin sensitivity in offspring from obese mothers seems to be driven by an increase in SkM GLUT4 expression [16, 18, 23, 26, 27]; however, improved glucose tolerance independent of the changes in GLUT4 expression has similarly been observed [29, 31]. This indicates that an improvement in glucose transport capacity is not the only mechanism responsible for improved glucose clearance. Offspring from exercising compared to sedentary mothers exhibit improved SkM insulin signaling cascade activation with insulin stimulation; this is evidenced by higher phosphorylation of Protein Kinase B, also known as AKT, a key mediator of insulin-stimulated glucose uptake [17]. In addition to the effects of maternal exercise on SkM, it is important to recognize that these adaptations extend to offspring liver, a major organ for regulating glucose disposal and production. Maternal exercise improves mature offspring hepatic insulin sensitivity and lowers hepatic glucose production during hyperinsulinemic-euglycemic clamp [16]. Similar effects have been observed in an in vitro model where isolated hepatocytes of offspring from exercising mothers exhibit enhanced glucose control across basal and insulin- and glucagon-stimulated states [31]. Greater glucagon-mediated hepatocyte glucose production and insulin-mediated inhibition of glucose production suggest that maternal exercise improves liver glucose metabolism across different physiologic states (fasted vs. fed) [31]. Interestingly, it is worth noting that this effect is observed in offspring from exercising mothers independent of maternal metabolic status (healthy or obese). This suggests that while metabolic enhancements may be present, they may not be evident with measurements at the whole-organism level considering the multifaceted input of several organs [31]. In rodent models, it is clear, that maternal exercise negates the effects of maternal obesity through enhancements in offspring glucose metabolism, which lowers the potential for glycemic dysregulation in subsequent generations.

2.2.3 Mitochondrial remodeling

Maternal exercise lowers SkM and liver triglyceride content in offspring from both healthy and obese mothers [24, 29, 31]. Lower SkM and liver triglyceride content will decrease the chance of lipid accumulation-induced impairments with insulin signaling and are suggestive of an enhanced oxidative capacity. Maternal exercise increases offspring SkM mitochondrial density, length, and mitochondrial DNA content [19, 34]. These mitochondrial alterations predominantly stem from the effects of maternal exercise on PGC-1α, a key mediator of mitochondrial functioning and biogenesis [19, 34]. Maternal exercise before and during pregnancy attenuates high-fat diet (HFD) induced PGC-1α promoter hypermethylation in offspring SkM, and is able to rescue a HFD induced decrease in PGC-1α gene expression [19, 27]. Interestingly, the effect of maternal exercise on PGC-1α expression has only been observed in adult offspring [27]. This, however, may be an artifact of the rapid proliferation and differentiation of SkM cells during early growth compared to mature SkM, when myogenic cells are quiescent and transcription of genes is predominantly influenced by gene methylation [27]. Higher PGC-1α expression in SkM increases expression of its downstream targets including cytochrome C, a central component of the electron transport chain, which potentiates improvements in the regulation of oxidative phosphorylation [27]. Additionally, in SkM of offspring from exercising mothers, greater cytochrome C oxidase and citrate synthase activities have been observed [34], suggesting that maternal exercise has an effect on mitochondrial oxidative capacity. It is worth noting that similar hypermethylation and lower mRNA expression of PGC-1α is seen in SkM of individuals with T2D [35]. This points to maternal exercise as a potential therapy to ameliorate the transgenerational transmission of mitochondrial dysfunction in humans, by increasing the oxidative capacity as well.

In liver, the maternal exercise induced increase in PGC-1α mRNA expression is accompanied by higher protein expression of phosphorylated AMP-activated protein kinase (AMPK), which is considered to be a master regulator of energy metabolism [36]. This AMPK-PGC-1α axis and its increase is paralleled by an increase in PPARα mRNA expression and is suggestive of a greater potential for fatty acid oxidation. Specifically, maternal exercise enhances gene expression of Acox1 and Acacb, enzymes involved in fatty acid handling and oxidation [36]. Interestingly, while improving the capacity for fatty acid oxidation, maternal exercise simultaneously decreases the potential for fatty acid storage by lowering PPARγ mRNA expression, a gene associated with hepatic steatosis [36, 37]. Further, greater phosphorylated AMPK expression in offspring from exercising mothers leads to greater phosphorylation of acetyl-CoA carboxylase which lowers the availability of malonyl-CoA, a precursor for fatty acid synthesis [36]. It is important to note that these adaptations on a cellular level extend to elicit whole-body protection and lead to lower BW gain and hepatic steatosis after pups are challenged with an obesogenic diet [36]. Overall, maternal exercise driven improvements of offspring mitochondrial bioenergetics are often seen as vital for proper metabolic functioning and resilience to metabolic challenges in adult life. These adaptations could influence the predisposition for the development of metabolic disease by altering mitochondrial substrate “preference” and oxidation capacity.

Maternal exercise increases the affinity for pyruvate and palmitoyl-CoA in offspring SkM mitochondria suggesting easier access of these substrates for the oxidative phosphorylation system (OXPHOS) [17]. Further, maternal exercise has no effect on the K_m for palmitoyl-carnitine, which suggests that maternal exercise might be acting specifically on CPT-1, a commonly altered enzyme in obesity-related diseases. Finally, a larger decrease in enzyme affinity is seen for palmitoyl-CoA compared to pyruvate suggesting that maternal exercise increases offspring SkM preference for fatty acid oxidation and potentially explains the previously described decrease in triglyceride content [17, 29]. In addition to altering SkM metabolic pathways, offspring from exercising mothers exhibit greater levels of liver mRNA expression of genes involved in pyruvate metabolism (Pklr, Pcx), the tricarboxylic acid cycle (Pdha1, Pdk4, CS, Idh3a, Mdh2), and fatty acid transport and oxidation (Cd36, Fatp4, Acox, Cpt1) [31]. Together, this data shows that maternal exercise induces an array of adaptations that enhance substrate handling and subsequently increase resilience against future metabolic disease.

Data regarding maternal exercise and offspring OXPHOS capacity is limited. Maternal exercise decreases complex II and III activity and increases complex IV activity [22]. Additionally, when ADP-stimulated respiration is measured in SkM mitochondria from offspring of exercising mothers, there seems to be no effect on complex I and complex I + II respiration; however, data regarding respiration through complex II only is inconsistent with maternal exercise resulting in a decrease or having no effect on complex II maximal respiration [22, 23]. Interestingly, in isolated liver mitochondria from offspring of exercising mothers, lower complex II and higher complex IV activity and content is observed, and accompanied by lower maximal respiration through complex I, II, and I + II. Interestingly, respiratory control ratio (RCR) is lower in offspring mitochondria from both liver and SkM when respiration is supported through complex I and complex I + II [22]. As an index of how coupled respiration is to ADP phosphorylation, this would suggest a lower capacity for phosphorylating respiration to offset electron leak; however, implications about the effect of maternal exercise on offspring mitochondrial efficiency cannot be made as RCR, when used as a proxy of mitochondrial coupling, does not always match the ATP/O ratio, which is a direct measure of mitochondrial coupling [38]. Data regarding alterations in offspring energy efficiency come from oxygen consumption rates in free living conditions. Accordingly, on the level of the whole organism, maternal exercise increases the basal oxygen consumption rate, subsequently protecting offspring from overnutrition-induced obesity by increasing their energy expenditure [20, 30] Together, the limited data suggests that maternal exercise results in adaptations in mitochondrial respiration, but no conclusive remarks can be made considering the inconsistencies between and limited number of studies.

2.2.4 Mitochondrial redox balance

While mitochondria are often described predominantly in the light of energy metabolism, it is important to recognize their function in maintaining redox homeostasis. Mitochondria are mediators of redox balance, and this is influenced by alterations to pro- and antioxidant systems. Disruption of the redox balance due to alterations in mitochondrial bioenergetics or the redox buffering capacity are considered to be an integral part in the etiology of metabolic disease (i.e., IR) [39]. Maternal exercise lowers hydrogen peroxide production with complex II only and complex I + II supporting substrates in both SkM and liver mitochondria [22]; however, the effects seen in SkM are inconsistent across studies indicating maternal exercise may not affect hydrogen peroxide emission [23]. Interestingly, SkM and liver mitochondria from offspring of exercising mothers are protected from reverse electron transport linked hydrogen peroxide emission [22]. Hydrogen peroxide emission via reverse electron flow is often associated with overnutrition and suggests that maternal exercise has a protective effect on offspring redox balance during future metabolic challenges such as overnutrition [39]. In addition to lower hydrogen peroxide emission and subsequently lower reactive oxygen species (ROS) production, maternal exercise enhances glutathione activity in blood and liver [22]. Further, offspring from exercising mothers have lower blood thiol content suggestive of a higher antioxidant capacity. These adaptations are paralleled with higher offspring liver alpha-tocopherol which increases free radical scavenging ability and decreases lipid peroxidation [40, 41, 42]. Maternal exercise further induces a mitochondrial fatty acid profile shift by increasing short-chain and decreasing long-chain fatty acid content [22]. These changes can be beneficial considering that short-chain fatty acids are more resistant to free radical attack and peroxidation and have a positive influence on redox signaling [43, 44]. Finally, maternal exercises increases offspring LON protease (an oxidative stress induced mitochondrial degradation catalyst) and TFAM induced autophagy; these changes are suggestive of a greater mitochondrial turnover rate and overall lower susceptibility to oxidative stress induced mitochondrial dysfunction [24, 34]. Together, these findings suggest that maternal exercise increases antioxidant capacity, decreases ROS production, and lowers the potential accumulation of less functional mitochondria in offspring.

Together, maternal exercise will protect offspring from maternal obesity induced metabolic derangements and has the capacity to increase offspring resilience against future metabolic challenges. Further, offspring metabolic adaptations (Figure 1) as a result of maternal exercise seem to be independent of body composition alterations. These adaptations include improvements in offspring glucose and fatty acid metabolism across two major metabolically active tissues, the liver and SkM. In part, these adaptations are linked to mitochondrial structure remodeling, enhanced bioenergetic function, and greater redox capacity. Finally, it is imperative to keep in mind that cellular metabolic programing precedes improvements detected at the whole-body level making in vitro assessments indispensable for the understanding of maternal exercise-induced fetal programing.

Figure 1.

Maternal exercise enhances offspring metabolism across two major metabolically active tissues, the liver and SkM. Offspring from exercising mothers have lower body weight (BW) and body fat (BF%) gain with age and exhibit enhanced whole body glucose tolerance. Additionally, maternal exercise leads to greater insulin sensitivity, mitochondrial remodeling, and improved bioenergetic function and substrate metabolism in peripheral tissue. Abbreviations: BW, body weight; BF%, body fat percentage; and OXPHOS, oxidative phosphorylation.

3. Human studies of maternal obesity and exercise effects on offspring metabolism

3.1 Effects of maternal obesity on offspring metabolism

While rodent models provide an insight into the effects of maternal exercise on progeny, a major obstacle is analogizing human and animal research considering the vast physiological difference between species. In humans, maternal obesity rates are rising and are in parallel with those of the general population [45, 46]. Pre-pregnancy obesity is likely to translate into excessive gestational weight gain, pre-eclampsia, gestational diabetes, and a greater propensity towards postpartum weight retention [47]. Moreover, maternal obesity increases the risk for congenital anomalies, fetal death, stillbirth, and neonatal, perinatal, and infant death [48, 49]. Increased maternal pre-pregnancy body mass index corelates with increased risk of offspring obesity [50]. Specifically, maternal obesity increases the odds of offspring obesity by 264%, while maternal overweight increases odds by 89% [50]. Neonates born to obese mothers are often large for gestational age with increased adiposity being a major determinant of fetal overgrowth [47]. Besides increasing adiposity, neonates of obese mothers have a higher propensity towards IR independent of maternal glycemia [51, 52]. Finally, maternal obesity is associated with an adverse lipid profile in offspring and an inclination towards the development of metabolic syndrome [53, 54, 55]. While this relationship between maternal and offspring metabolism is readily accepted, limitations in the understanding of epigenetic mechanisms governing infant metabolic reprograming remain. Moreover, the biological mechanisms behind metabolic adaptations that govern offspring metabolic phenotypes remain to be elucidated.

The use of umbilical cord derived mesenchymal stem cells (MSCs) has been recognized as a model for the investigation of metabolic programming of the human offspring donor. This model capitalizes on the multilineage potential of MSCs and their ability to differentiate into various lineages of mesenchymal tissue (muscle, fat, etc.) [56, 57, 58, 59, 60, 61]. The phenotype of MSCs reflects that of the donor rendering it as an advantageous in vitro model to study offspring phenotypes on a molecular level [62, 63, 64, 65, 66]. MSCs from offspring of obese mothers exhibit a greater potential for adipogenesis associated with greater PPAR-γ, FABP4, and lipid content in adipogenically differentiated cells [65]. Further, evidence of lower β-catenin protein content paired with a lower inhibitory phosphorylation of GSK-3β in undifferentiated MSCs suggests a greater shift in cell commitment towards an adipocyte rather than myocyte lineage and will subsequently increase the propensity of the fetus towards greater adiposity [65]. Accordingly, greater MSC adipogenesis potential is positively correlated with infant body fat mass [65]. In line with greater potential for fetal adiposity, MSCs from offspring of obese mothers exhibit greater lipid accumulation and lower capacity for fatty acid oxidation when undergoing myogenesis, which will potentiate ectopic lipid accretion [64]. It is worth noting that fatty acid oxidation in MSCs from offspring of obese mothers is “less efficient” with more substrate flux towards incomplete rather than complete oxidation [64, 66]. Additionally, maternal obesity induces a MSC phenotype with lower metabolic flexibility and a decreased ability to meet metabolic demands, demonstrating primary deficits in fatty acid oxidation [66]. These factors have previously been observed in SkM of humans with non-gravid obesity and have been associated with the development of IR [67, 68, 69]. This suggests that maternal obesity may alter offspring metabolism with a predisposition towards metabolic disease (i.e., obesity). Accordingly, beta-oxidation decrements in myogenically differentiated MSCs from offspring of obese mothers are correlated with infant adiposity suggesting that fetal adiposity is in part predetermined by alterations in the fetal metabolic phenotype [63]. These inherent differences in MSC lipid metabolism seemingly stem from differential mitochondrial expression and methylation of genes involved in mitochondrial fatty acid metabolism and respiration (i.e., OXPHOS) and are correlated with neonatal adiposity [62, 63]. Particularly, alterations in lipid metabolism are associated with lower AMPK content and activation and hypermethylation of genes involved in fatty acid oxidation (i.e., ACC2, CPT1A) [64]. Overall, this data suggests that maternal obesity reprograms the offspring metabolic phenotype by increasing propensity towards adiposity, which, in part, occurs through the lowering of oxidative capacity. Moreover, considering that similar alterations are seen with non-gravid obesity, it is reasonable to postulate that this phenotype will predispose offspring to metabolic perturbations later in life. Accordingly, it is necessary to further our understanding of lifestyle interventions that could counteract the intergenerational transmission of metabolic disease. Specifically, non-pharmacological interventions, such as exercise could have a tremendous impact on fetal metabolic programing with overall metabolic disease lowering properties highlighting the need for more research studies. While alterations of the MSC phenotype as a consequence of maternal obesity have been shown, the effects of maternal exercise on offspring metabolic reprograming remain understudied in humans, especially on a molecular level.

3.2 Effects of gestational exercise on offspring metabolism

Prenatal maternal exercise elicits an array of positive benefits for both mother and offspring. Maternal aerobic exercise lowers the risk for the development of gestational diabetes mellitus and lowers gestational weight gain in both healthy and mothers with gestational diabetes [5, 7, 8, 70]. Further, there is an inverse relationship between gestational weight gain and exercise duration and volume with benefits increasing as exercise volume approaches American College of Obstetricians and Gynecologists (ACOG) recommendations of 500 MET-minute weekly [7, 8, 71]. Maternal exercise alone reduces the risk of macrosomia and offspring being large for gestational age without increasing risk of pre-term birth or low birth weight [8, 72, 73]. Further, maternal exercise may have a greater influence on birth weight reduction in maternal obesity, however, evidence remains weak [72, 73]. Similarly, the association of maternal exercise and birth weight remains weeak across multiple meta-analysis including women of all body mass index categories and seems to be driven predominantly by exercise volume [8, 72, 73]. Accordingly, the exercise-induced reduction of offspring birth weight is predominantly observed with exercise volumes over 810 MET-min, which is much greater than the 500 MET-min per week recommendation by ACOG [72]. Finally, birth weight reductions observed with maternal exercise are often not clinically significant (i.e., >300 g) making it hard to conclude if prenatal exercise has a significant effect on fetal birth weight [74, 75]. Additionally, while body weight can be influenced by fat and lean mass, maternal exercise does not seem to effect child morphometrics based on two recent meta-analyses [73, 76]. Nonetheless, while alterations in birth weight are not significant, there is evidence to support the beneficial effects of a prenatal healthy lifestyle (i.e., normal BMI, regular exercise, etc.) on the risk of offspring childhood (child age of 9–14) obesity [77]. Overall, while prenatal exercise influences maternal gestational weight gain, the effects of maternal exercise on offspring birth weight and body composition seem to be minimal. Accordingly, and in line with rodent studies, exercise induced body composition alterations might be secondary to other metabolic improvements and may decrease the risk of obesity development with aging.

The positive effects of exercise extend to maternal metabolic health through improvements in lipid and glucose metabolism. Data suggests that maternal exercise improves maternal metabolism during pregnancy and subsequently alters pregnancy outcomes and the metabolic phenotype of offspring. Physical activity during pregnancy reduces the rise of low density lipoprotein and triglyceride, and lowers delivery and neonatal complications [78, 79, 80, 81, 82]. Maternal blood lipids are associated with infant adiposity and alterations in MSC metabolism in offspring from mothers with obesity [63, 64, 78] suggesting a potential in-utero influence of maternal lipids on fetal metabolic programing. Recently shown, maternal aerobic exercise during gestation may alter the MSC phenotype, however, improvements in lipid oxidation, oxidation efficiency or uptake, and accumulation were not significant [83]. While the lack of effect is surprising based on previously described effects in rodent models and MSCs from offspring of mothers with obesity, it must be noted that exercising mothers were seemingly healthy and thus potentially “diluting” the effect of maternal exercise on offspring metabolic reprograming. Accordingly, the positive effects of maternal exercise on offspring MSC lipid metabolism may be pronounced in situations where an adverse intrauterine environment is instilled by maternal metabolic disease (i.e., obesity) [63, 64, 65, 83]; however, there are currently no studies exploring these effects.

Aerobic exercise during pregnancy significantly improves maternal glucose metabolism with a greater effect in women with overweight, obesity, and gestational diabetes [84, 85]. In particular, maternal aerobic exercise lowers insulin levels late in pregnancy and reduces the increase in blood insulin levels from 15- to 36-weeks of gestation [86]. Maternal dysglycemia, with or without gestational or type 2 diabetes, has been associated with adverse pregnancy outcomes (i.e., preeclampsia), offspring outcomes (i.e., excessive fetal growth, congenital abnormalities), and an overall increase in postpartum risk of development of T2D in both mother and offspring [87, 88, 89]. Evidence for maternal dysglycemia altering offspring metabolism can be further observed at the level of MSCs where metabolic derangements coincide with derangements in maternal glycemic control (i.e., HOMA-IR) [64]. Further, maternal aerobic exercise increases insulin-mediated glycogen synthesis rates in undifferentiated MSCs suggestive of greater insulin sensitivity [83]. This effect was paralleled with greater insulin-mediated phosphorylation of signaling marker GSK-3β in undifferentiated MSCs. Together, these promising effects could counter the previously described transmission of IR in the case of maternal glucose dysglycemia (i.e., during obesity). In addition to glycogen synthesis, enhanced glucose oxidation efficiency and partitioning of glucose towards oxidation is observed in both undifferentiated and myogenically differentiated MSCs from offspring of aerobically trained mothers. Interestingly, a trend towards a greater capacity for glucose oxidation was observed in myogenically differentiated but not undifferentiated MSCs [83]. It is worth noting that there is greater expression of complex I in myogenically differentiated MSCs, which could in part influence the greater glucose oxidation rates considering that glucose oxidation increases the input of electrons to complex I of mitochondria [83]; however, this effect needs to be further elucidated. As previously described, obesity driven metabolic derangements lead to less efficient mitochondria with a lower oxidative capacity; thus, it is possible that a greater capacity to oxidize glucose may attenuate the transmission of decrements in glucose metabolism across generations. The partitioning of glucose towards oxidation, rather than glycolytic intermediates (i.e., lactate), would lower the propensity towards metabolic disease considering that a lower oxidation capacity and greater lactate production have been linked with T2D [90, 91, 92]. While this data is associative in nature, the importance of exercise in improving the metabolism of both mother and offspring is clear (Figure 2).

Figure 2.

Maternal obesity increases pregnancy complications and introduces an array of metabolic derangements in mother and offspring health. Maternal gestational exercise improves many aspects of obesity-induced metabolic alterations and enhances maternal and offspring metabolism. Abbreviations: GWG, gestational weight gain; GDM, gestational diabetes mellitus; MSCs, mesenchymal stem cells; FA, fatty acid; AMPK, AMP-activated protein kinase; and IR, insulin resistance.

4. Transfer of maternal exercise induced effects on offspring and exercise modalities

The effects of exercise, both acute and chronic, are partly mediated through the production and secretion of bioactive molecules termed cytokines. With exercise, an array of these metabolic factors are released by SkM influencing muscle metabolism as well as crosstalk between SkM and other organs. While extensive reviews have been published on this topic [93, 94], it is worth mentioning that these factors could mediate fetal programing as well. However, this is contingent on their placental blood barrier permeability. Many cytokines (i.e., IL-15, BAIBA, BDNF, Irisin, etc.) have an influence on energy metabolism and an overall positive effect on metabolic disease [93, 94]; however, the involvement of these cytokines in regulating offspring metabolic phenotypes is not yet understood. Recently, the effects of cytokine apelin have been shown to drive maternal exercise-induced metabolic reprogramming in offspring [19, 95]. Maternal exercise elevates apelin signaling which facilitates fetal muscle development and subsequently increases PGC-1α promoter demethylation, mitochondrial biogenesis and remodeling, and mitochondrial capacity [95]. This data suggests that maternal exercise-induced cytokine release could have a direct effect on fetal development by inducing specific adaptations that will later shape offspring metabolism. Accordingly, it is reasonable to postulate that different modes of exercise, based on their differences in cytokine expression profiles and differential metabolic demands [96, 97, 98], could have differing effects on offspring metabolic reprograming.

Exercise modes separate into aerobic and muscular strength training where activity is performed against a low resistance for a longer time or against high resistance for a short duration, respectively. These exercise modalities differ in the adaptations they elicit and are driven by the different energetic demands experienced during activity. During an acute bout of exercise, substrate oxidation is predominantly driven by the intensity and duration of exercise. There is a shift from predominantly fatty acid oxidation during prolonged low-moderate intensity exercise towards an almost exclusive reliance on glycolytic substrates during high-intensity exercise bouts. Aerobic training is often associated with improvements in cardiorespiratory fitness via an increase in maximal oxygen consumption and mitochondrial biogenesis. Specifically, aerobic exercise increases SkM mitochondrial protein synthesis, density, and oxidative function, which subsequently improves endurance capacity [99]. With this, it is not surprising that aerobic exercise results in a greater abundance of proteins involved in mitochondrial ATP production, TCA cycle, transport, and oxidation of fatty acids which are predominantly regulated through PGC-1α expression [99]. In contrast, while the effects of resistance exercise on these parameters are minimal, resistance training increases muscle size, strength, myofibrillar protein synthesis, and anaerobic capacity significantly more than aerobic exercise [99]. Both modalities improve glucose handling and are beneficial for improving glucose control predominantly through enhancing insulin sensitivity (i.e., greater GLUT4 expression) [99, 100, 101]. Additionally, aerobic training improves cardiovascular profiles and decreases adiposity, while resistance training seemingly has a very limited effect on either of these parameters [99]. Overall, while both modalities reduce the risk and lower the derangements of metabolic disease (i.e., obesity), the effects by which aerobic and resistance training influence metabolism vary to a great extent. With this in mind, it is reasonable to postulate that depending on the maternal exercise mode, effects on offspring metabolic reprograming will differ; however, research directly comparing the effects of maternal exercise modes on offspring metabolic health outcomes remains scarce especially with maternal muscular strength training.

While muscular strength training during pregnancy is safe and recommended, most research assessing the effects of prenatal exercise on offspring metabolic health utilizes aerobic only or a combination of aerobic and strength training. While these two exercise modes are beneficial for both maternal and offspring health, a delineation of their independent effects on offspring metabolic health is currently not possible [70]. Further, a comparison of the independent effects of maternal aerobic or strength training on offspring metabolism is primarily limited due to the lack of the studies utilizing maternal strength training [69]. To date, it is shown that a combination of aerobic and strength training during pregnancy increases cardiorespiratory fitness and muscle strength more so than aerobic or strength training alone [70]. Further, combined training has the most significant impact on decreasing gestational weight gain; however, more studies are needed to confirm these findings [70]. Evidence is similarly weak with inconsistent findings on the effects of combined training on improvements in birth weight; however, it is important to note that all exercise interventions increase the chance of the offspring having a normal birth weight and reduce the risk of macrosomia [70]. In conclusion, gestational exercise is safe and recommended considering the resulting array of positive metabolic changes in both mother and offspring.

5. Conclusion

Considering the prevalence and burden of obesity and T2D in today’s society, it is crucial to identify new targets and treatment approaches to combat these diseases. As discussed, maternal exercise before and/or during pregnancy has a critical influence on offspring metabolism and can decrease their risk of development of metabolic disease later in life. While the current understanding of the precise mechanisms underlying these developmental influences is not fully understood, future work in this area holds immense potential to prevent and alleviate instances of obesity and improve the life-long health of the child.