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Introduction
Obesity has been increasing worldwide and constitutes a significant public health problem since it favors the development of several comorbidities1.
Studies in the United States have reported that over 60% of women of reproductive age are overweight at conception, and approximately 30% are obese. In Mexico, obesity prevalence has increased from 32.4% in 2012 to 36.1% in 2018, more prevalent in women (40.2%) and reaching up to 38.5% in women of reproductive age (20-49 years)2. This prevalence is relevant as a significant population of infants will be exposed to an obesogenic environment during critical prenatal development3,4.
Several epidemiological studies and experimental models have argued that maternal health and nutritional status during pregnancy and lactation play critical roles in the programming of neural circuits that regulate the energy balance and behavior of their offspring5-11. Furthermore, it has been described that the progeny of obese mothers shows an increased incidence of hypertension, dyslipidemia, hepatic inflammation, obesity, and leptin and insulin resistance, increasing the risk of metabolic syndrome4,6,12.
In most studies, obesity in animal models is induced by a high-fat diet, as the dietary fat content is considered one of the main factors responsible for increased adiposity. In rodents and humans, a relationship has been demonstrated between the level of dietary fat consumed and body weight or fat gain, and a positive correlation between the amount of consumed fat and the incidence of obesity. Therefore, dietary fat may be the main component responsible for the induction of an obese phenotype13-16.
The Developmental Origins of Health and Disease hypothesis postulates that exposure to environmental challenges during critical periods of development leads to fetal adaptations that become maladaptive when exposed to environmental and metabolic stressors17. Because of this phenomenon, several systems appear to be sensitive to fetal programming5.
Skeletal muscle represents about 40% of total body mass and is a prominent regulator of glucose and fatty acid metabolism18. The early programming of skeletal muscle is relevant, given its capacity to generate metabolic adaptations that can regulate its functionality, performance, and strength. In addition, the metabolism of energy substrates in the skeletal muscle is a crucial element in homeostasis19. The intrauterine environment has been described as a critical determinant of muscle mass20. Evidence has shown that the involvement of skeletal muscle at an early age is crucial because low muscle mass and strength can contribute to adverse outcomes from early developmental stages, even as early as infancy21. This evidence has established maternal obesity as a model for inducing skeletal muscle damage in several animal models22.
This review addresses the current evidence describing the consequences of fetal exposure to an obesogenic maternal diet on skeletal muscle tissue, focusing on changes in tissue composition, alterations in signaling pathways related to glucose and fatty acid metabolism, mitochondrial biogenesis, and oxidative phosphorylation. It should be mentioned that obesogenic diets differ among studies. Typically, diets containing > 30% of total energy as fat lead to the development of obesity23; however, obesity has been induced in animals with fat-containing diets as low as 13% of total energy24 or as high as 85%25. Diet-induced obesity (DIO) models consist of diets with a variable fat content (% kcal of fat). The most commonly used DIO models range from 45% to 60% of fat content16.
Although the obesogenic diets in the studies reviewed here are heterogeneous, the obese maternal phenotype secondary to the administration of the obesogenic diet during gestation has been demonstrated, confirming that the fetus is exposed to this maternal phenotype. Finally, on the content of other macronutrients in the diets, some authors have discussed a positive relationship between the level of fat in the diet and the degree of obesity, even without controlling for the amount of protein in the diet23. This relationship suggests that, although other macronutrients, such as protein, are relevant in skeletal muscle composition, the maternal obese phenotype associated with the consumption of a high-fat diet may be sufficient to induce changes in the skeletal muscle of the offspring, regardless of the unfortunately underestimated protein content of the diets mentioned in the reviewed studies.
Impact of a maternal high-fat and high-carbohydrate diet on the skeletal muscle of the offspring
The number of muscle fibers is partially determined since prenatal development. After birth, muscle fibers may undergo a process of hypertrophy, but hyperplasia occurs to a lesser extent; therefore, effects on muscle development during the embryonic and fetal periods may generate deleterious effects in postnatal life21. An inadequate nutrient supply during prenatal development can lead to impaired muscle development in the product, resulting in reduced muscle mass and function in postnatal life (Table 1). This effect has been evidenced in a murine model of mothers on a high-fat diet, in which the progeny showed a reduced weight of the tibialis anterior muscle at 15 weeks after birth26.
Table 1 Effects of maternal obesogenic diet on skeletal muscle morphology and function in offspring
| Animal model | Maternal diet | Muscle | Age | Effect on the progeny | Ref |
|---|---|---|---|---|---|
| Mouse | High-fat diet (45% kcal from fat) | Tibialis anterior | 15 weeks after birth | Lower muscle weight | 26 |
| Mouse | Sucrose-rich diet (26% simple sugars, 5% fat, 12% protein w/w) | Tibialis anterior | 3 months after birth | Reduction in muscle mass | 27 |
| Rat | High-fat diet with fast-absorbing carbohydrates [protein 24.2 g, fat 20.5 g, carbohydrates 49.4 g/100 g diet (carbohydrates: 81.9% sucrose, 18.1% fructooligosaccharides w/w)] | Gastrocnemius | 3 and 7 weeks after birth | Decrease in muscle weight | 19 |
| Rat | High-fat diet with fast-absorbing carbohydrates [protein 24.2 g, fat 20.5 g, carbohydrates 49.4 g/100 g diet (carbohydrates: 81.9% sucrose, 18.1% fructooligosaccharides w/w)] | Extensor digitorium longus and tibialis | 7 weeks after birth | Decrease in muscles weight | 19 |
| Rat | High-fat diet (45% kcal from fat, 20% kcal from protein, 35% kcal from carbohydrates) | Gastrocnemius | 150 days after birth | Decrease in total protein content in muscle | 28 |
| Mouse | High-fat diet (45% kcal from fat) | Gastrocnemius | 20 weeks after birth | Increase in muscle triglyceride content | 29 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Decrease in intramuscular triglycerides, increase in fatty acids and intramyocellular phospholipids | 30 |
| Mouse | High-fat diet (40% kcal from fat, 23% kcal from protein, 37% kcal from carbohydrates) | — | From 7 to 25 weeks after birth | Decrease in the capacity to resist voluntary exercise | 18 |
| Mouse | High-fat diet (40.2% kcal from fat, 23% kcal from protein, 36.8% kcal from carbohydrates) | — | From 4 weeks after birth | Reduced exercise performance and reduced physical training efficiency | 20 |
| Mouse | Sucrose-rich diet (26% simple sugars, 5% fat, 12% protein w/w) | — | 3 months after birth | Reduction in locomotor activity | 27 |
Ref: reference.
Several studies have demonstrated the effects of a high-sugar maternal diet on the offspring. Samuelsson et al.27 showed a reduction in tibialis anterior muscle mass in female offspring in a murine model of mothers fed a high-sugar diet. Meanwhile, Salto et al.19 observed that a high-fat maternal diet with fast-absorbing carbohydrates significantly decreased gastrocnemius muscle weight in the offspring. In contrast, this effect was not observed with a high-fat diet with slow-absorbing carbohydrates. This finding was observed at early and late stages after birth, indicating a long-term decline in muscle mass. Interestingly, at a later stage (7 weeks after birth), the offspring also showed a reduction in muscle weight of both the extensor digitorum longus and the tibialis anterior muscles19.
In addition to a decrease in skeletal muscle weight, other changes in muscle composition have been described. For example, a reduction of total protein content in the gastrocnemius muscle was observed in a murine model in response to exposure to an obesogenic environment in utero28. Modifications in lipid content in this muscle characterized by an increase in triglycerides were also identified29. Similarly, in a non-human primate animal model, a Western diet before and during pregnancy induced a decrease in intramuscular triglycerides in the offspring but an increase in fatty acids and intramyocellular phospholipids30.
Along with the alterations in skeletal muscle composition, the progeny of mothers fed a high-fat or high-sugar diet show a decreased capacity for voluntary exercise endurance18, a significant reduction in exercise performance, low efficiency in physical training20, and reduced locomotor activity27, indicating functional alterations in skeletal muscle due to the obesogenic environment.
An obesogenic maternal diet and alterations in carbohydrate and lipid metabolism in the skeletal muscle of the offspring
The relevance of maternal programming in skeletal muscle, carbohydrate, and lipid metabolism has been shown in several studies (Table 2). In a Japanese macaque model of offspring from mothers fed a high-fat diet, a decrease in insulin-induced glucose uptake was observed in the rectus femoris and soleus muscles, which was a long-term effect. The effect was also found in the rectus femoris muscle; IRS1 (insulin receptor substrate 1) and p110a (phosphoinositide 3-kinase subunit) content decreased in fetal muscles, along with a subsequent decrease in IRS1 phosphorylation during adolescence. Authors also showed a reduction in insulin-stimulated phosphorylation of Akt (also known as protein kinase B) downstream of insulin receptor activation17. Another study in a murine model demonstrated that the offspring of obese mothers showed decreased IRS1 phosphorylation in skeletal muscle31. In the offspring of mothers fed a high-fat diet with fast-absorbing carbohydrates, a decrease in Akt phosphorylation was also observed in both early and late stages19. These same effects were demonstrated when the mothers were fed only a high-fat diet31.
Table 2 Effects of maternal obesogenic diet on carbohydrate and lipid metabolism in offspring skeletal muscle
| Animal model | Maternal diet | Muscle | Age | Effect on the progeny | Ref |
|---|---|---|---|---|---|
| Japanese macaque | High-fat diet (36.6% kcal from fat) | Rectus femoris and soleus | Gestational day 130 | Decreased insulin-induced glucose uptake in fetal muscles | 17 |
| Japanese macaque | High-fat diet (36.6% kcal from fat) | Soleus | 14 months after birth | Decreased insulin-induced glucose uptake in muscle | 17 |
| Japanese macaque | High-fat diet (36.6% kcal from fat) | Rectus femoris | Gestational day 130 | Decreased IRS1 and p110α (PI3K subunit) in the fetal muscle | 17 |
| Japanese macaque | High-fat diet (36.6% kcal from fat) | Rectus femoris | Gestational day 130 | Decreased insulin-stimulated Akt phosphorylation in fetal muscle | 17 |
| Japanese macaque | High-fat diet (36.6% kcal from fat) | Soleus | 14 months after birth | Decreased insulin-stimulated Akt and IRS1 phosphorylation in muscle | 17 |
| Rat | High-fat diet with fast-absorbing carbohydrates [protein 24.2 g, fat 20.5 g, carbohydrates 49.4 g/100 g diet (carbohydrates: 81.9% sucrose, 18.1% fructooligosaccharides w/w)] | Gastrocnemius | 3 and 7 weeks after birth | Decreased Akt phosphorylation in muscle | 19 |
| Mouse | High-fat diet (protein 20.8 g, fat 23.6 g, carbohydrates 41.2 g/100 g diet) | Soleus | 28 days after birth | Decreased Akt and IRS1 phosphorylation in muscle | 31 |
| Mouse | High-fat diet (protein 20.8 g, fat 23.6 g, carbohydrates 41.2 g/100 g diet) | Soleus | 82 days after birth | Decreased insulin-induced Akt and IRS1 phosphorylation in muscle | 31 |
| Mouse | High-fat diet (protein 20.8 g, fat 23.6 g, carbohydrates 41.2 g/100 g diet) | Soleus | 28 days after birth | Increased p-JNK, p-IKK, and PTP1B expression | 31 |
| Mouse | High-fat diet (protein 20.8 g, fat 23.6 g, carbohydrates 41.2 g/100 g diet) | Soleus | 82 days after birth | Increased p-IKK expression | 31 |
| Mouse | High-fat diet (protein 20.8 g, fat 23.6 g, carbohydrates 41.2 g/100 g diet) | Soleus | 82 days after birth | Increased insulin-induced PTP1B and PEPCK expression | 31 |
| Rat | High-fat and sucrose diet (23.5% total fat, 9.83% saturated fat, 20% sucrose, 23.3% protein w/w) | Soleus | 12 months after birth | Increased Akt total protein, reduction in the levels of phosphorylation at position Ser473 | 32 |
| Rat | High-fat diet (23-36% fat, 19.4% protein, 44.9-40% carbohydrate w/w) | Gastrocnemius | 19 days after birth | Decreased mRNA expression of GLUT4 in muscle | 33 |
| Rat | High-fat diet (15% fat, 18.9% casein, 0.3% l-cysteine, 48.3% corn starch, 3.3% maltodextrin, 13% sucrose, 4.7% cellulose, 4.3% mineral mix, 1.1% vitamin mix w/w) | Soleus | 3 and 8 weeks after birth | Decreased mRNA and protein expression of GLUT4 in muscle | 34 |
| Sheep | Hypercaloric diet (170-190% high metabolizable energy requirements) | Quadriceps | 4 months after birth | Increased expression of GLUT4 mRNA, decreased protein expression of GLUT4 in muscle | 35 |
| Sheep | Hypercaloric diet (170-190% high metabolizable energy requirements) | Quadriceps | 4 months after birth | Increased GSK3α protein expression and decreased phosphorylation of GSK3a at the Ser21 position | 35 |
| Rat | High-fat diet (15% fat, 18.9% casein, 0.3% l-cysteine, 48.3% corn starch, 3.3% maltodextrin, 13% sucrose, 4.7% cellulose, 4.3% mineral mix, 1.1% vitamin mix w/w) | Soleus | 3 and 8 weeks after birth | Decreased mRNA expression of AdipoR1 in muscle | 34 |
| Rat | High-fat diet with fast-absorbing carbohydrates [protein 24.2 g, fat 20.5 g, carbohydrates 49.4 g/100 g diet (carbohydrates: 81.9% sucrose, 18.1% fructooligosaccharides w/w)] | Gastrocnemius | 3 weeks after birth | Decrease in the levels of AMPK phosphorylation in muscle | 19 |
| Rat | High-fat diet with fast-absorbing carbohydrates [protein 24.2 g, fat 20.5 g, carbohydrates 49.4 g/100 g diet (carbohydrates: 81.9% sucrose, 18.1% fructooligosaccharides w/w)] | Gastrocnemius | 7 weeks after birth | Decrease in the levels of mTOR phosphorylation in muscle | 19 |
| Mouse | High-fat diet (60% kcal from fat) | Quadriceps | 12 months after birth | Decreased Co×4 and Cytc mRNA expression | 36 |
| Rat | High-fat diet with fast-absorbing carbohydrates [protein 24.2 g, fat 20.5 g, carbohydrates 49.4 g/100 g diet (carbohydrates: 81.9% sucrose, 18.1% fructooligosaccharides w/w)] | Gastrocnemius | 7 weeks after birth | Increased expression of PKM2 | 19 |
| Mouse | High-fat diet (40.2% kcal from fat, 23% kcal from protein, 36.8% kcal from carbohydrates) | Quadriceps | 12 weeks after birth | Decreased levels of CD36 and FAS mRNA in the muscle | 20 |
| Mouse | High-fat diet (40.2% kcal from fat, 23% kcal from protein, 36.8% kcal from carbohydrates) | Quadriceps | 12 weeks after birth | Decreased mRNA expression of GLUT1 in muscle | 20 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Increased protein expression of CPT-1β and VLCAD. Decreased protein expression of SCHAD | 30 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Increased mRNA expression of PDK4 | 30 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Increase in lipidic peroxidation in muscle. | 30 |
| Non-human primat | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Increased expression of 4HNE-modified proteins in muscle | 30 |
AdipoR1: adiponectin receptor 1; Akt: protein kinase B; AMPK: AMP-activated protein kinase; Co×4: cytochrome C oxidase subunit 4; CPT-1β: carnitine palmitoyl transferase 1β; Cyt: cytochrome; GLUT1: glucose transporter type 1; GLUT4: glucose transporter type 4; GSK3α: glycogen synthase kinase 3; IRS1: insulin receptor substrate 1; mTOR: mammalian target of rapamycin; p-JNK: phospho-c-Jun N-terminal kinase; p-IKK: phospho-IκB kinase; PDK4: pyruvate dehydrogenase kinase 4; PEPCK: phosphoenolpyruvate carboxykinase; PI3K: phosphoinositide 3-kinase subunit; PKM2: pyruvate kinase muscle isozyme; PTP1B: protein-tyrosine phosphatase 1B; SCHAD: short-chain 3-hydroxy acyl-CoA dehydrogenase; VLCAD: very long-chain acyl-CoA dehydrogenase.
Other models have found increased Akt protein levels but reduced phosphorylation at the Ser473 position, indicating that there could be a compensatory mechanism evidenced by increased Akt protein expression due to its reduced activation32. Notably, some insulin signaling cascades and glucose uptake changes do not occur in exacerbated adiposity, hyperinsulinemia, or systemic insulin resistance, suggesting that alterations in insulin-mediated signaling may be elicited before systemic effects17.
Alterations in the insulin-mediated signaling pathway may be reflected in a decreased skeletal muscle glucose uptake capacity. Murine offspring of obese mothers show decreased expression of GLUT4 (glucose transporter type 4) in skeletal muscle33,34. This diminished GLUT4 expression could be due to deficient insulin-mediated signaling. In a sheep model in which dams were fed a hypercaloric diet, the skeletal muscle of the offspring showed high GLUT4 mRNA expression, whereas protein expression of this molecule was decreased. The authors proposed that the increased expression of the GLUT4 gene transcript could compensate for the reduced protein level35.
Similarly, alterations in other molecules involved in insulin signaling have been described. In a sheep model, a higher expression of GSK3a (glycogen synthase kinase 3) accompanied by a decreased phosphorylation of GSK3a at the Ser21 position was observed in the skeletal muscle offspring of mothers fed a hypercaloric diet. As GSK3a is a negative modulator of insulin actions, a decrease in the activity of this molecule could be related to abnormal insulin-mediated glucose metabolism35. De Fante et al.31 conducted a study in murine offspring from a maternal obesity model and observed increased expression of p-JNK (phospho-c-Jun N-terminal kinase), p-IKK (phospho-IkB kinase), PTP1B (protein-tyrosine phosphatase 1B), and PEPCK (phosphoenolpyruvate carboxykinase) in the soleus muscle. Increased expression of PTP1B has been associated with an attenuation of insulin-mediated signaling, and PEPCK is an enzyme involved in gluconeogenesis.
In addition, lower expression of the AdipoR1 (adiponectin receptor 1) transcript was observed in offspring exposed to a high-fat maternal diet, suggesting a dysfunction in the signaling of this adipokine in the skeletal muscle, which could contribute to insulin resistance and obesity in postnatal life34. The maternal obesogenic environment also induces a decrease in the phosphorylation levels of AMPK (AMP-activated protein kinase), a kinase associated with muscle energy status, and a reduction in the phosphorylation levels of mTOR (mammalian target of rapamycin)19. Furthermore, other modifications have also been found in the expression of molecules such as Cox4 (cytochrome c oxidase subunit 4) and Cyt (cytochrome) genes involved in energy metabolism36.
As for other parameters related to the metabolism of energy substrates, some studies found that the offspring of obese mothers preferentially use glucose as an energy source, even despite alterations in the insulin-signaling pathway. In a murine model of dams fed a high-fat and fast-digesting carbohydrates diet, the skeletal muscle of the offspring showed increased expression of PKM2 (pyruvate kinase muscle isozyme), indicating an increased dependence on glucose for energy19. In other in vivo models, a significantly decreased expression of CD36 and FAS mRNA (essential for fatty acid metabolism, and GLUT1 (glucose transporter type 1, a transporter for basal glucose uptake) was observed in the quadriceps muscle of offspring in a model of obesity20.
However, the preference of offspring skeletal muscle to utilize lipid substrates has also been evidenced. In non-human primates whose mothers were fed a Western diet, CPT-1b (carnitine palmitoyl transferase 1b) protein, a rate-limiting enzyme for oxidation of long-chain fatty acids, increased to 2-fold in the skeletal muscle of the offspring. Similarly, the expression of the PDK4 (pyruvate dehydrogenase kinase 4) gene and VLCAD (very-long-chain acyl CoA dehydrogenase) protein, specific for long-chain fatty acid oxidation, increased. In contrast, SCHAD (short-chain 3-hydroxy acyl-CoA dehydrogenase) protein expression decreased. Furthermore, increased fetal muscle lipid peroxidation along with increased 4HNE-modified proteins was found in skeletal muscle in this model30.
Based on these findings, it is suggested that maternal obesity combined with a Western diet downregulates genes involved in glucose utilization and upregulates the ability of cells to oxidize fatty acids30.
An obesogenic maternal environment modifies mitochondrial function in the offspring
Mitochondrial function is considered an essential process in skeletal muscle function. Moreover, several studies have shown that obesogenic exposure in utero could lead to alterations of this organelle (Table 3).
Table 3 Effects of maternal obesogenic diet on mitochondrial function in offspring skeletal muscle
| Animal model | Maternal diet | Muscle | Age | Effect on the progeny | Ref |
|---|---|---|---|---|---|
| Mouse | High-fat diet (16% fat, 33% simple sugars, 15% protein) | Tibialis anterior | 30 days after birth | Increased number of copies of mitochondrial DNA in muscle | 37 |
| Rat | Hypercaloric diet (40% excess calories, 220 kcal/kg/day) | Gastrocnemius | 130 days after birth | Reduced mRNA expression of PGC1α, SIRT1, and Mfn1 | 38 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Increased mRNA expression of GADD45, SIRT3, UCP2, and UCP3 in muscle | 30 |
| Mouse | High-fat diet (40% kcal from fat, 23% kcal from protein, 37% kcal from carbohydrates) | Quadriceps | 25 weeks after birth | Decreased protein expression of the oxidative phosphorylation complex I in muscle | 18 |
| Rat | High-fat and sucrose diet (23.5% total fat, 9.83% saturated fat, 20% sucrose, 23.3% protein w/w) | Soleus | 12 months after birth | Decreased protein expression of the oxidative phosphorylation complexes I, II, and V in muscle | 32 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Increased activity of the oxidative phosphorylation complexes I and IV. Increased expression of ATP synthase subunits ATP5C1 and ATP5A1 in muscle | 30 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Decreased activity of the citrate synthase in muscle | 30 |
| Non-human primate | Western diet (37% kcal from fat) | Gastrocnemius | Gestational day 130 | Decreased mitochondrial/nuclear DNA ratio in muscle | 30 |
GADD45: growth arrest and DNA damage; Mfn1: mitofusin 1; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SIRT1: sirtuin 1; SIRT3, sirtuin 3; UCP2: uncoupling protein 2; UCP3: uncoupling protein 3.
Maragkoudaki et al.37 described increased mitochondrial DNA copy number in the skeletal muscle of offspring in a murine model of maternal obesity. Mitochondrial DNA copy number has been described as a determinant of reduced energy expenditure and glucose tolerance in the offspring of obese mothers. Increased mitochondrial genetic material has been related to early exposure to reactive oxygen species in maternal hyperinsulinemia secondary to obesity and could reflect a compensatory mechanism responding to decreased mitochondrial function. In addition, it has been proposed that increased mitochondrial DNA could reflect a maladaptive response and lead to a non-functional response to oxidative stress and maternal hyperglycemia.
Decreased expression of PGC1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), a transcriptional regulator related to energy metabolism and mitochondrial biogenesis, SIRT1 (sirtuin 1) and Mfn1 (mitofusin 1), both involved in the mitochondrial repair process in the muscle, has been described in the offspring of a murine model of maternal obesity38.
Moreover, other alterations related to oxidative stress and mitochondrial function have been reported. A significantly increased expression of the gene encoding the GADD45 (growth arrest and DNA damage) protein, a marker of cellular stress, was described in a non-human primate model, along with an increased expression of SIRT3 (sirtuin 3), a mitochondrial protein associated with the induction of the antioxidant system. Increased expression of the uncoupling proteins UCP2 (uncoupling protein 2) and UCP3 (uncoupling protein 3), which have been associated with increased fatty acid oxidation in murine models, was also found. These data suggest that the Western obesogenic maternal diet increases the production of reactive oxygen species and activates signaling pathways responsible for protection against cellular stress in fetal muscle30.
Other studies in animal models have shown mitochondrial alterations related to oxidative phosphorylation, an essential function in skeletal muscle metabolism. Reduced complex I of the electron transport chain has been observed in the offspring of a murine model of maternal obesity with a high-fat diet, indicating that this condition attenuates the ability to generate a proton gradient necessary for ATP synthesis. This process is critical during endurance exercise and could explain the altered muscle performance18,32.
Similarly, decreased protein expression of complexes II and V has been found in another model of maternal obesity, which also suggests a reduction in mitochondrial function and ATP production. This mechanism could contribute to the development of insulin resistance and lead to increased generation of reactive oxygen species, lipid peroxidation, and release of proinflammatory cytokines32.
Conversely, in non-human primates, an increase in the activity of complexes I and IV of the oxidative phosphorylation chain together with an increased expression of ATP synthase subunits, was found in the skeletal muscle of the offspring of obese mothers fed a Western diet. Interestingly, despite the increased activity of specific electron transport chain components, a decrease in citrate synthase activity was observed, while the mitochondrial/nuclear DNA ratio was up to 2-fold lower in the offspring of obese mothers fed a Western diet. Despite the increased activity of the complexes, the efficiency of electron transport chain coupling was significantly lower in the offspring of obese mothers fed a Western diet30.
In conclusion, maternal obesity has been postulated as an inducer of damage in multiple fetal organs and tissues, including skeletal muscle. Skeletal muscle has movement and locomotion functions and, in parallel, plays a vital role in the metabolism of energy substrates. Given its multiple functions, the secondary consequences of exposure to an obesogenic environment in utero could severely impact postnatal life.
As described in this review, maternal obesity induces changes in skeletal muscle morphology and composition, which affect physical performance. In addition, exposure to an obesogenic diet induces alterations in carbohydrate and lipid metabolism. Changes in the signaling pathway of insulin receptors involved in glucose uptake by tissues, as well as modifications in the utilization of fatty acids as a source of energy, are prominent. Interestingly, some studies have proposed the existence of compensatory mechanisms generated to counteract the deleterious effects of maternal obesity in the offspring, highlighting the plasticity of skeletal muscle tissue and its capacity to create adaptive responses to external stressors.
Fetal programming is a complex process in which multiple factors are involved. Questions about the causal mechanisms of this phenomenon and the magnitude of the effects produced by fetal exposure to an obesogenic environment in prenatal life remain unanswered. Undoubtedly, in the future, there will be proposals to help explain this phenomenon and approaches to counteract and prevent the deleterious effects of maternal obesity on the offspring.
