Key words
developmental programming - exercise - pregnancy - mitochondria
Introduction
It is well established that a sedentary lifestyle is associated with an increased
incidence of chronic diseases, such as type 2 diabetes, cancers, cardiovascular diseases,
and comorbidities [1]. To reduce this burden, effective interventions need to be discerned and implemented.
Physical activity is an accessible positive lifestyle habit that can contribute to
weight loss, changes in body composition, and improved cardiorespiratory fitness [2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]. Physical activity interventions have shown to be successful in increasing an individual’s
quality of life [10]
[11] and continue to support the need for physical activity across all races, ethnicities,
genders, and age groups. Once thought to be detrimental to the developing fetus, exercise
is now recommended for most pregnant women [12]. The notion of increasing physical activity interventions in pregnancy is gaining
traction in that this period is a crucial timepoint to improve offspring outcomes.
In 1989, the epidemiologist David Barker coined the Developmental Origins of Health
and Disease Hypothesis by linking small for gestational age infants with increased
incidence of cardiovascular disease in adulthood [13]. This hypothesis postulates that if the fetus is exposed to unfavorable environmental
conditions in utero and during the early stages of development, the fetus will undergo permanent metabolic
adaptations that allow for survival in the unfavorable intrauterine environment. However,
these adaptations may also lead to the development of diseases after birth [14]. Excess maternal weight gain and obesity during pregnancy have been known to contribute
to poor fetal and maternal outcomes related to risk factors/incidence for cardiometabolic
disease [15] making pregnancy a potentially viable target for intervention. The cyclic nature
of cardiometabolic diseases continuing from mother to child and the subsequent perpetuation
of metabolic disease across generations marks a potentially dire need for interventions
to halt this vicious cycle. Luckily, pregnancy has been identified to have the potential
to be a “teachable moment” for mothers [16] due to the increased contact with healthcare providers and increased concern for
the health of the fetus. The purpose of this review is to provide a synopsis on physical
activity as a method of improving neonatal metabolic health. This review will begin
with general guidelines on physical activity during pregnancy and a brief section
on maternal responses. It will then turn its attention toward offspring responses
to maternal physical activity that encompass changes in whole-body and cellular metabolism.
Finally, potential areas of investigation for future research will be presented.
Exercise During Pregnancy
Exercise During Pregnancy
Physical activity recommendations
Pregnant women can benefit from physical activity to a similar extent as nonpregnant
women [17], and various forms of physical activity have been deemed safe and appropriate during
pregnancy [12]
[17]
[18]
[19]. The American College of Obstetricians and Gynecologists (ACOG) currently recommends
that women who begin their pregnancy with a “healthy lifestyle” (e. g., exercise,
proper nutrition, nonsmoking) continue to maintain those healthy habits throughout
their pregnancy [12]. Women not achieving “healthy lifestyle” habits should accordingly be encouraged
to establish healthier habits and routines throughout the pre-pregnancy and pregnancy
periods [12]. During pregnancy, 150 minutes of moderate intensity aerobic activity per week is
recommended [12]
[19]. Those who habitually engaged in vigorous intensity aerobic activity or who were
physically active before pregnancy can continue their activities [12]. Consistent with recommendations from the American College of Sports Medicine (ACSM)
[20], a combination of aerobic and resistance exercise appears to deliver benefits for
both the mother and infant. This review will highlight beneficial changes with primarily
aerobic exercise/physical activity.
For women with uncomplicated pregnancies, fears of physical activity and exercise
resulting in adverse outcomes have yet to be validated [21]
[22]
[23]
[24]. While these exercise recommendations have been in place for over a decade, the
prevalence of active pregnant women is still alarmingly low. Among pregnant women,
walking is the most frequently reported activity, usually occurring during the first
trimester [25]
[26]. Across the United States however, it is estimated that as few as 15.8% of women
are physically active at the recommended level during pregnancy [27]. Only 21.5% of a cohort of healthy pregnant women in Ireland reported meeting the
current ACOG recommendations of physical activity with 11.7% reporting no physical
activity at all [28]. Studies across other countries report similar numbers [29]
[30]
[31]. Further, for those who do participate in structured physical activity during pregnancy,
the intensity, frequency, and volume may not be at levels sufficient to incur the
adaptations induced with an active lifestyle [32]. Aerobic exercise interventions have been found to minimize gestational weight gain
when combined with diet or with exercise alone [33]. However, a recent multi-site randomized clinical trial that managed to increase
physical activity showed a modest effect between the intervention and control group
(−1.59 kg) on total gestational weight gain [34] and did not prevent gestational diabetes in the mother [35]. Nonetheless, exercise has been shown to be protective against disorders such as
preeclampsia and should be promoted due to several beneficial physiological adaptations
[36]
[37]
[38]
[39]
[40].
Maternal responses during pregnancy
The scope of this article is offspring outcomes in response to maternal exercise;
therefore, this review will briefly touch upon maternal adaptations. It should be
noted that the effects of exercise on pregnant women has been reviewed extensively
elsewhere [41]
[42]
[43]. During a healthy pregnancy, many physiological adaptations occur in the cardiovascular
system to support adequate oxygen and nutrient supply to the fetus. Cardiac output
is increased up until term by 30- to 50 percent due to both an increase in stroke
volume and heart rate (HR) [44]. An additional increase in tidal volume is responsible for a 30- to 40 percent increase
in minute ventilation in pregnancy. Although many of these changes would assume a
rise in oxygen consumption, there is only a slight 15- to 20 percent increase, resulting
in an increase in alveolar and arterial PaO2 (partial pressure of oxygen) and a fall in PaCO2 (partial pressure of carbon dioxide) levels [45]. These and other positive adaptations that occur with pregnancy are amplified with
regular physical activity and exercise. Cardiovascular fitness, measured by maximal
oxygen uptake (VO2max), is rarely reported with pregnancy due to theoretical risk of fetal distress.
However, there are instances where this has been performed in pregnancy [46]. As central responses (e. g. stroke volume, HR, cardiac output, etc.) do not differ
significantly between pregnant and nonpregnant women during submaximal exercise [47], it seems that alterations in the periphery are at play.
Many of the peripheral cardiovascular changes seen in physically active mothers help
to ensure the appropriate trafficking of nutrients to the developing fetus. Because
the placenta is the central organ linking the fetus and the maternal environment,
it is responsible for bridging the effects of external stimuli on maternal health
status to the fetus. Placental growth is largely dictated through substrate availability
and blood flow and is calculated as the product of substrate concentration measured
in arterial blood and blood delivery to the placental bed, with a heavy focus on glucose
[48]
[49]
[50]. With maternal exercise, blood flow is diverted from the placenta to exercising
muscles and skin [51] which is proportional to the exercise intensity and muscle mass used [48]. After the cessation of exercise, blood flow quickly returns to normal [48]. Due to the invasive nature of measuring fetoplacental blood flow, exercise-induced
blood redistribution has not been measured in humans. Animal data translated to humans,
however, indicates blood flow redistribution associated with exercise intensities
up to 95% VO2max does not compromise the fetus. Repeated bouts of exercise at 95–100% VO2max, however, are associated with negative effects on fetal growth confirming submaximal
exercise does not compromise blood delivery to the fetus [43]
[52]
[53]
[54].
Additionally, maternal exercise impacts placental gene expression to optimize fetal
nutrient delivery and fetoplacental growth [55]
[56]
[57]. Those who performed strenuous exercise during pregnancy had increased T-type amino
acid transporter 1 (TAT1), neutral amino acid transporter A (ASCT1), mitochondrial branched chain amino transferase (mBCAT), and glutamine sythetase (GLUL) placental expression indicating maternal exercise enhances amino acid transport
pathways [58]. Genes associated with fatty acid metabolism are similarly altered with maternal
exercise [59]
[60]
[61]. Mothers who met physical activity guidelines also showed improvements in the expression
of genes involved in glucose transport as well as mammalian target of rapamycin (mTOR)
and insulin signaling in the placenta, further highlighting the benefits of maternal
exercise in the relationship between the maternal environment, placenta, and fetal
environment [55]. Finally, reactive oxygen species (ROS) production in the placenta was also lowered
with exercise suggesting improved oxygen metabolism [57]. All these beneficial adaptations are imparted in the offspring to ensure adequate
growth.
Effects of Maternal Exercise on Offspring
Effects of Maternal Exercise on Offspring
Anthropometrics
Infant birth weight allows for a crude measurement of newborn health and is an indicator
of the fetal environment. Both low and high birth weights have been shown to be related
to obesity, metabolic disease, and cardiovascular disease later in life [62]
[63]
[64]. The pregnancy field has outlined a clear U-shaped association between offspring
birth weight and long-term metabolic complications [65]. Many of these have been outlined in epidemiological studies. For example, studies
on famine in pregnancy concluded that infants exposed to conditions of malnutrition
have reductions in glucose tolerance later in life [66]. In the case of maternal obesity, infants have increases in childhood body mass
index (BMI), adiposity, and increased risk of diabetes as adults [67]
[68]. Therefore, there is a need to fine tune this U-shaped association with lifestyle
interventions, with one of the most prominent interventions being exercise.
Largely conflicting evidence exists for the support of structured maternal exercise
affecting infant birth weight. Maternal exercise during pregnancy has been associated
with increased infant lean mass compared to infants of sedentary mothers [69]. Other studies have shown that maternal exercise has been shown to be associated
with a reduction in the upper quantiles of birth weight distributions [70]
[71]. There are reports showing that maternal exercise may not affect infant weight at
birth [72]; however, a recent study has shown that infants exposed to maternal exercise had
increased adiposity at 7-years of age [69]. Finally, a recent meta-analysis conducted by Guillemette et al. concluded prenatal
maternal exercise does not significantly impact infant birth weight nor fat mass nor
large-for-gestational-age risk [73]. These studies highlight the continued need for more studies focused on maternal
exercise and infant birth weight. Indeed, studies of regular aerobic exercisers and
those who engage in vigorous physical activities, such as elite athletes, show that
infants were born with lower birth weight [74]
[75]. Thus, there might be a dose-response relationship between maternal exercise, again
lending credence to the fine-tuned nature of maternal pregnancy outcomes and the U-shape
association that also exists in other aspects of pregnancy such as that in gestational
weight gain [76].
Research on other forms of physical activity, such as non-structured leisure time
physical activity (LTPA) has also been studied. Research has shown that LTPA does
not increase the chance of a small for gestational age newborn [77]. At a minimum, adherence to physical activity guidelines has been shown to reduce
risk of delivering large for gestational age newborn with no effect on delivering
small for gestational age [71]
[78]
[79]
[80]. LTPA is thought to normalize birth weight into a healthy range by normalizing maternal
blood glucose, reducing maternal insulin resistance, and altering placental blood
flow and nutrient delivery [32]
[49]
[81]
[82]. While remaining cautious to not over-interpret these results, enough evidence of
lasting benefits of LTPA during pregnancy exists to encourage larger, prospective
studies to understand if prenatal interventions might be an effective way of preventing
childhood obesity in humans.
With limited data on long-term outcomes of offspring to exercising mothers in humans,
rodent studies may provide additional insights. In mice, maternal exercise improves
offspring body composition [83]
[84] or shows no effect [72]
[85]. Interestingly, when fed a high-fat diet, offspring of trained mothers gained less
weight and stored less fat compared to offspring of untrained mothers, which suggests
a protective effect of exercise [72]
[83]. While rodent findings may not be applicable in human research, due to factors such
as uterine structure, length of gestation, size of litters, the idea of exercise as
a protective measure to support a more favorable body composition is persuading.
Cardiovascular fitness
Aerobic fitness (VO2max) is the product of central cardiac output and the peripheral oxygen extractability
of the working tissues [86]. Exercise training in non-pregnant cohorts increases aerobic fitness via coordinated
adaptations of these central and peripheral components and the majority of work in
this area has been substantiated in the animal literature. Prior data has shown that
rodent offspring born to mothers who underwent aerobic exercise before and during
pregnancy, have higher aerobic fitness [87] and physical activity levels [88] providing evidence that maternal exercise is capable of programming the offspring’s
cardiovascular system including cardiac output, macrovascular compliance, and skeletal muscle oxidative capacity. These are summarized in the subsequent paragraphs.
A hallmark adaptation of chronic exercise training is an increase in stroke volume
and increased heart rate variability [89]
[90]
[91]
[92]
[93]. Although the effect of maternal exercise on offspring cardiovascular remodeling
is not yet fully understood, exercise training has been shown to improve ejection
fraction and left ventricular mass [94]. Exercise training also prevents obesity-induced impairments in cardiac output by
attenuating pathological left ventricular hypertrophy and preserving the ejection
fraction of adult rodent offspring [95]. While the mechanisms are not clear, studies have shown that maternal exercise epigenetically
programs the offspring’s cardiac transcriptome, increasing the expression and activity
of genes involved in mitochondrial biogenesis [94]
[96] – an important characteristic for many offspring peripheral adaptations.
Although indirect, aerobic exercise generally improves cardiac function by decreasing
afterload via structural and functional changes that increase vascular compliance
[97]
[98]
[99]. Maternal exercise has been shown to improve endothelium-dependent vasodilation
in porcine offspring at birth, but this effect was blunted in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, suggesting
increased nitric oxide bioavailability is responsible for this improvement [100]. However, follow-up studies indicated the effects of maternal exercise on offspring
endothelium are transient and no longer evident in the months following birth in either
healthy [101] or high-fat fed swine offspring [102]. Furthermore, endothelium-independent relaxation in the adult offspring exposed
to maternal exercise was reduced, suggesting maternal exercise may accelerate the
age-related decline in smooth muscle compliance [101]. In rodents, maternal exercise did not alter the offspring’s endothelial-dependent
or -independent relaxation in the months following delivery [103]. Similarly, Boonpattrawong et al. reported that maternal exercise alone had no effect
on offspring vascular function but was protective against maternal obesity and high
fat post-weaning diet. Interestingly, aerobic exercise improved nitric oxide bioavailability
in the offspring fed the Western diet, despite the groups having similar levels of
nitric oxide synthase expression. The authors determined maternal exercise improved
aortic one-carbon metabolism, which could have indirectly improved nitric oxide bioavailability
by reducing the uncoupling of nitric oxide synthase in the mice fed the high fat diet
[104]. Finally, Li et al., observed that maternal exercise reduced smooth muscle vasoconstriction
responses to norepinephrine and Bay K8644 (a Ca2+ channel agonist) of offspring born to spontaneous hypertensive mother rats. DNA bisulfite
sequencing revealed maternal exercise increased methylation of the calcium voltage-gated
channel subunit α-1C (Cacna1c) promoter, preventing it from being upregulated during the programmed hypertension
[105]. Taken together, these data suggest maternal exercise can serve a protective role
in vascular function, but this protection is only evident with gestational obesity
and/or postnatal insults (e. g., high-fat diet).
Despite extensive work being conducted in animal models, it is still unclear if these
results can be translated to humans. Limited data stems from a recent pilot study
revealing moderate-intensity aerobic exercise in healthy pregnant women reduced the
carotid intima-media thickness in offspring, suggesting improved vascular compliance
[106]. Furthermore, there have been few studies to track the effectiveness of maternal
exercise on cardiac function in humans. May et al. determined maternal aerobic exercise
reduces fetal heart rate and increases heart rate variability at 36 weeks of gestation
[107]. Follow-up analysis by this group revealed the increase in heart rate variability
was retained one month following delivery, providing evidence of a lasting cardiovascular
phenotype [108]. Whether or not these other mechanisms, such as the nitric oxide system, are at
play in humans remains to be discovered.
Skeletal muscle oxidative capacity
The peripheral component, oxygen extractability (A-VO2), of working skeletal muscle increases with aerobic training via increases in capillary
density and mitochondrial biogenesis [109]
[110]
[111]. Like cardiovascular changes, most of this work has been shown using animal models.
Liu et al. was the first to establish a programming effect of maternal exercise on
the oxidative capacity of rodent skeletal muscle. They and others [87] noted that exercise prior to and during pregnancy did not alter skeletal muscle
capillary density but did increase markers of mitochondrial biogenesis including mitochondrial
density and the enzymatic activity of citrate synthase and cytochrome C oxidase in
the offspring [112]. Further, Siti et al. reported that maternal exercise in rodents increased the enzymatic
activity of electron transport system complexes II and III, reduced substrate-specific
H2O2 production, and increased ADP-stimulated respiration rates in offspring skeletal
muscle [113]. Peroxisomal proliferator-activated receptor y coactivator-1 alpha (PGC-1α) has been termed the “master regulator” of mitochondrial
biogenesis and plays a key role in several exercise-induced adaptations [114]
[115]
[116]
[117]. Therefore, it can be proposed that maternal exercise could epigenetically modify
the PGC-1α gene (Ppargc1a), to ‘prime’ PGC-1α expression in the offspring skeletal muscle. Son et. al provided
the first evidence that exercise alone reduced the methylation status of the offspring’s
skeletal muscle Ppargc1a promoter, increasing the expression of PGC-1α. Importantly, the authors noted several
other markers of mitochondrial biogenesis and oxidative capacity increased, including
increased VO2max, proportion of oxidative muscle fiber (higher IIa/lower IIx), mitochondrial DNA
(mtDNA) content, and markers of mitochondrial fission/fusion [87]. Taken together, there is accumulating evidence in rodents to suggest maternal exercise
enhances the oxidative capacity of the skeletal muscle of offspring via intrinsic
changes in the mitochondrial phenotype. However, due to the invasive and longitudinal
nature of these studies, these results have yet to be substantiated in humans.
Substrate metabolism
The increased prevalence of sedentary lifestyles and Western-style diets has led to
a parallel rise in metabolic diseases including type 2 diabetes, metabolic syndrome,
and cardiovascular disease. A distinctive feature of these diseases is disordered
substrate metabolism and the eventual ectopic deposition of substrates and excessive
spillover of metabolites [118]. These aspects have significant relevance to the pregnancy field as well [119]. Generally, exercise interventions that aim to improve aspects of substrate handling
is concomitant with enhancements in mitochondrial content/function to resolve the
perturbations in metabolic stress. Due to the robust changes in the skeletal muscle
mitochondrial phenotype elicited by maternal exercise as described in the section
above, there is a vested interest in determining whether it can protect the offspring
from metabolic dysfunction and disease in the current obesogenic environment.
Thus far, several investigations have determined maternal exercise can reduce the
offspring’s susceptibility to metabolic diseases by rescuing glucose intolerance,
hyperlipidemia, endocrine dysregulation, and global oxidative stress in offspring
born to mothers with obesity or that were fed a high-fat diet during pregnancy [115]
[120]
[121]
[122]
[123]
[124]
[125]. These have been shown in models of rodent exercise where mice were trained preconception
and in combination of preconception and during pregnancy. Data suggests maternal exercise
acts on tissues responsible for regulating whole-body metabolism including the skeletal
muscle, liver, and pancreas.
The skeletal muscle is responsible for 70–80% of postprandial glucose disposal, thus
development of skeletal muscle insulin resistance is a key tenant in the pathogenesis
of type 2 diabetes [126]. Carter et al. was the first to show maternal exercise improves ex vivo glucose uptake in the skeletal muscle, but not adipose tissue of the rat offspring
[127]. Although the exact mechanisms have yet to be elucidated, data suggests maternal
exercise relieves skeletal muscle Ppargc1a promoter hypermethylation, induced by maternal high-fat diet, which was associated
with elevations in the mRNA expression of glucose transporter 4 (Glut4), cytochrome c (Cyt c), and cytochrome c oxidase subunit 4 (Cox4)
[115]. Furthermore, a recent study indicated maternal exercise protects the offspring’s
oxidative capacity by rescuing their mitochondria phenotype and fiber type distribution.
The authors determined maternal exercise was responsible for demethylating the Ppargc1a promoter and increasing PGC-1α expression, in contrast to the repression evident with a maternal sedentary lifestyle and high-fat
gestational diet [87]. Taken together, maternal exercise improves the substrate handling of the offspring
skeletal muscle and offers protection from certain disruptions associated with maternal
obesity and Western-style gestational diets. However, Quiclet et. al found that maternal
exercise did not rescue the glucose tolerance in rat offspring fed a high fat/high
sucrose diet. In situ mitochondrial respiration assays revealed maternal exercise improved substrate affinity
(Km) for palmitoyl-CoA and pyruvate in sedentary, chow-fed offspring, but not in mice
fed a high-fat/high-sucrose diet [83]. Therefore, it is still unclear if maternal exercise can protect the offspring skeletal
muscle from postnatal dietary insults. Moreover, no investigations have been done
to determine if these results can be translated to humans.
In coordination with the skeletal muscle, liver metabolism and pancreatic β-cell function
plays an obligatory role in regulating whole body metabolic health and therefore has
been investigated in the context of maternal exercise. Stanford et al. recently determined
maternal exercise improved glucose tolerance in mice born to mothers fed a standard
chow or high-fat diet [120]. Interestingly, their ex vivo experiments revealed no effect of maternal exercise on the skeletal muscle, but instead
a robust remodeling of the hepatic insulin sensitivity and glucose production phenotype.
Although the mechanisms have yet to be elucidated, studies from the same group show
evidence of hepatic mitochondrial biogenesis in the offspring born to mothers who
exercised. Although attention has been centered on determining the effect of maternal
obesity and gestational diabetes on offspring β-cell function [128]
[129]
[130]
[131], Zheng et al. was the first to show that the combination of pre-gestational paternal
exercise and pre-and during-gestational exercise preserved β-cell mass, size, and
islet morphology in offspring born to parents fed a high-fat diet [132].
To summarize, maternal exercise has been shown to improve cardiovascular function,
skeletal muscle oxidative capacity, and whole-body substrate metabolism partly as
a result of tissue-specific improvements in skeletal muscle, liver, and pancreatic
phenotypes. It is believed that epigenetic modifications underpin these improvements,
specifically in genes that affect mitochondrial outcomes of these tissues. Unfortunately,
most of these findings are derived from animal studies and thus, it is still unclear
if these results can be translated to humans. These specific types of studies are
wrought with challenges in human cohorts due to the invasiveness of tissue sampling
procedures. Often, human studies are limited to the presence/absence of metabolites
or hormones in cord blood and tissue. Thus, there is a need to identify new avenues
for future studies that explore the transmission and signaling behind maternal and
fetal health and disease in the context of human tissues and metabolism.
Recommendations for Future Studies
Recommendations for Future Studies
Intrauterine microenvironment
Previously, exercise has been shown to induce robust changes in circulating factors
that affect the tissue’s microenvironment. To date, the most studied exercise “factors”
are the cytokines released from skeletal muscle, termed myokines. There are presently
600 skeletal muscle myokine species that have been identified [133], and targeted approaches aim to understand the effects of myokines in remodeling
skeletal muscle metabolism. For example, interleukin 6, brain-derived neurotrophic
factor, and interleukin 15 have been shown to 1) be secreted from skeletal muscle
[134]
[135]
[136], 2) increase in circulation following exercise [134]
[135]
[137]
[138]
[139], and 3) independently improve mitochondrial density and/or function [140]
[141]
[142]. Importantly, these myokines help mediate the skeletal muscle-to-organ crosstalk
and therefore may play a role in fetal programming resulting from maternal exercise,
depending on their permeability through the placental-blood barrier. Recently, the
novel myokine and adipokine known as apelin has been shown to mediate several of the
skeletal muscle phenotype changes that occur in mice offspring born to mothers who
exercised during pregnancy [87]. In this study, maternal exercise increased levels of apelin, which subsequently
increases mitochondrial biogenesis and oxidative capacity in the offspring. Like apelin,
other undiscovered myokines and/or adipokines, which are now termed “exerkines” in
the field when they are secreted in response to exercise, may be signaling from mother
to infant and lend support to the notion of maternal exercise improving offspring
metabolic health.
Maternal donation of mtDNA
Mitochondria are originally descendent from endosymbiotic bacterium and this derivation
from symbiotic ancestors allows the maintenance of their own genome (mtDNA) [143]
[144]. mtDNA consists of a DNA ring of approximately 16570 nucleotides and contains 37
genes [145] but is responsible for transcription of 13 essential electron transport chain (ETC)
proteins, 2 rRNAs, and 22 tRNAs [143]. The remainder of the nearly 1200 proteins that make up mitochondria require nuclear
transcription and subsequent import into appropriate mitochondrial compartments resulting
in a finely tuned coordination between mtDNA and nuclear DNA.
Unlike the nuclear genome, mtDNA is inherited strictly through a maternal inheritance
pattern in eukaryotes where only the oocyte contributes mtDNA to the offspring [141]. Several mechanisms are recognized for the elimination of paternal mtDNA from the
embryo and include a genetic bottleneck, autophagy post-fertilization, ubiquitin-protease
pathways, and altered paternal mitochondrial transcription factor A (TFAM) expression
[146]. In addition, while exclusive maternal donation of mitochondria and mtDNA is generally
acknowledged, a few, exceptional cases of biparental inheritance of mtDNA in humans
exist [147]. This lack of recombination of mtDNA and its unique inheritance pattern thus allows
for an accumulation of transmitted mutations which can lead to severe diseases in
the offspring.
When maternal obesity was studied across three generations of mice, its effects could
be tracked across all three generations alongside mitochondrial changes in morphology,
bioenergetics, and dynamics [116]. The first generation of female offspring (F1) showed peripheral insulin resistance,
increased intramuscular lipid content, mitochondrial dysfunction, and impaired mitochondrial
dynamics in skeletal muscle. Oocyte mitochondria from the F1 mice also showed deranged
morphology, reduced mtDNA copy number, and impaired mitochondrial dynamics. These
were also apparent in the subsequent two generations. This propagation of mitochondrial
impairments across generations is not restricted to skeletal muscle. A follow-up study
by this group showed that maternal obesity in mice results in transgenerational cardiac
mitochondrial deficiencies as well [148]. Elegant in vitro fertilization studies from another group have shown that the oocyte at the time of
fertilization is susceptible to the intrauterine environment [149]. Whether or not this is generating changes in mtDNA or some nuclear aspect remains
to be discovered and is the central crux to understanding the inheritability of the
mitochondrial phenotype. Nonetheless, the initial insult is presently thought to stem
from changes in oocyte mitochondria, particularly issues with mitophagy in the oocyte
[150], that propagate to mitochondria that are present in all tissues/organs. Finally,
it is not certain in rodents or humans if exercise is protective in rescuing a deleterious
mitochondrial phenotype that is seen in maternal obesity. With new evidence of transmission
of mitochondrial impairment and as mtDNA codes for critical bioenergetic genes, any
potent approaches of improving mitochondrial health could lead to substantial advancements
of offspring health.
Umbilical cord-derived mesenchymal stem cells
Human trials examining the effects of maternal exercise on offspring have primarily
measured body composition and epigenetic outcomes in placental biospecimens such as
umbilical cord and cord blood. Although much has been gained from rodent models, several
discrepancies exist including a gestational period that is significantly shorter than
humans as well as differences in placental physiology including estrogen synthesis/release
[151], miRNA profile [152], expression of cell surface markers for trophoblast invasion [153], and accumulation of diet-specific metabolites [154]. Thus, it remains unclear if rodent findings can be translated to humans.
Non-invasive means to examine the effects of maternal exercise on offspring skeletal
muscle metabolism need to be implemented in humans. Primary human skeletal muscle
cells (SKMcs) have been used to investigate cell-autonomous mechanisms that underly
the effects of lifestyle interventions including exercise [155], as well as the pathophysiology of diseases including diabetes [156], obesity [157]
[158], and peripheral arterial disease [148]. For example, SKMcs derived from exercise-trained subjects retain the hallmark adaptations
seen in vivo including, elevations in lipid handling capacity [159]
[160], oxidative capacity [155], and insulin sensitivity [161]. Thus, it is believed the phenotype expressed in vitro is the result of lasting metabolic programming which occurs in vivo. Therefore, it is plausible to suggest that the metabolic programming in SKMcs results
from extrinsic changes in the tissue microenvironment, similar to what may be occurring
in the intrauterine environment. Performing invasive measures such as muscle biopsies
in young infants and children is impractical, making it difficult to understand the
tissue-specific effects of maternal programming unique to exercise training. To test
these hypotheses, researchers must identify a primary cell niche that can be noninvasively
obtained and exists beyond the placental-blood barrier.
Recently, blood and umbilical cord-derived mesenchymal stem cells (MSCs) have gained
attention in regenerative medicine because of their ability to differentiate into
several cell types including chondrocytes, adipocytes, and skeletal myocytes [162]. Importantly, MSCs are of fetal origin and thus, a mesodermal stem cell lineage
that contributes to the fetal development of several peripheral tissues and are the
primary stem cell lineage responsible for fetal myogenesis as well as postnatal skeletal
muscle growth and repair. Therefore, MSCs also offer the potential to gain insight
into the metabolic phenotype of the developing skeletal muscle at birth and possibly
how it will be maintained into adulthood. Recently, Boyle et al. indicated that MSCs
from offspring born to obese mothers have lower rates of fat oxidation and elevated
rates of lipid deposition [163]. These same MSCs were differentiated into an adipogenic phenotype and measured for
the quantity of fat stored in these cells. Interestingly, this fat storage phenotype
was shown to correlate positively with infant fat mass, which is direct support for
translating this model to the phenotype of the infant. Interestingly, when stratified
by oxidation rates, offspring with low MSC oxidation rates had higher adiposity and
fasting plasma insulin levels in vivo, providing evidence that maternal obesity has lasting negative implications for the
metabolic phenotype of the infant [164]. Although maternal physical activity has been shown to have a beneficial effect
on rodent offspring, it has yet to be determined whether this is evident in humans
and elicited primarily by the intrauterine environment. Thus, MSCs may bridge the
gap for future investigations into this area and may be used as an in vitro model for myogenic outcomes but also for exploring the inheritance of the maternal
mitochondrial phenotype.
Conclusion
The aim of the present review was to examine the current knowledge in the field of
exercise in pregnancy as it relates to the mother and developing fetus and identify
gaps in the literature (summarized in [Fig. 1]
). Animal studies have outlined several mechanisms through which the metabolic health
of offspring is improved through maternal exercise and have established inheritance
of metabolic impairments that track across multiple generations. Through these studies,
mitochondria seem to be key organelles in the progression of metabolic health across
generations. Exerkines may be a new research area of understanding how maternal exercise
may signal changes to the developing fetus. In addition, MSCs present themselves as
a potential and relevant model to gain insight into this cellular and metabolic programming
of offspring. With these models, exercise scientists may soon have the necessary tools
to explore the advantageous mechanisms in humans that exercise elicits from mother
to offspring. There is a dire need to translate these findings to human cohorts as
exercise during pregnancy maybe be a viable nonpharmacological strategy for prevention
of metabolic diseases at the earliest timepoint – while in the womb.
Fig. 1 The physiological effects of exercise during pregnancy on maternal and infant outcomes.
Maternal exercise promotes increases in cytosolic and intracellular calcium (Ca2+) concentrations, and increases AMP/ATP ratio, which may result in signaling skeletal
muscle (SkM) contraction and cell signaling. Both subsequent SkM and SkM mitochondrial
adaptations to maternal exercise during pregnancy are not yet clearly defined. In
addition, exerkine release (blue dots) into maternal blood results in subsequent placental
exposure to these molecules. While placental adaptations to maternal exercise are
still thoroughly unknown, exerkines could pass the placental barrier and mediate changes
in infant outcomes. Epigenetic programming of the offspring’s metabolic health is
suggested to occur with maternal exercise, and mesenchymal stem cells (MSCs) are proposed
to be a primary cell model for highlighting the infant’s potential skeletal muscle
and mitochondrial adaptations. In addition, due to the maternal donation of mitochondria,
the potential role of exercise training as a means of improving offspring mitochondrial
health warrants further investigation. Question marks identify all of these areas
that are currently gaps in the literature and open to future research directions.
This figure was created using BioRender.com.
