Moderately decreased maternal dietary energy intake during pregnancy reduces fetal skeletal muscle mitochondrial biogenesis in the pigs
© The Author(s) 2016
Received: 24 February 2016
Accepted: 15 June 2016
Published: 23 June 2016
Mitochondria are of major importance in oocyte and early embryo, playing a key role in maintaining energy homeostasis. Epidemiological findings indicate that maternal undernutrition-induced mitochondrial dysfunction during pregnancy is associated with the development of metabolic disorders in offspring. Here, we investigated the effects of moderately decreased maternal energy intake during pregnancy on skeletal muscle mitochondrial biogenesis in fetal offspring with pig as a model.
Pregnant Meishan sows were allocated to a standard-energy (SE) intake group as recommended by the National Research Council (NRC; 2012) and a low-energy (LE) intake group. Fetal umbilical vein serum and longissimus muscle samples were collected for further analysis on day 90 of pregnancy.
Sow and fetal weights and the concentrations of serum growth hormone (GH) and glucose were reduced in LE group. Maternal LE diet decreased the messenger RNA (mRNA) expression of genes involved in mitochondrial biogenesis and function such as peroxisome proliferator-activated receptor gamma coactivator 1α (PPARGC1A), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), β subunit of mitochondrial H+-ATP synthase (ATB5B), sirtuin 1 (Sirt1), and citrate synthase (CS). The protein expression of PPARGC1A and Sirt1, intracellular NAD+-to-NADH ratio, and CS activity was reduced in LE group, and accordingly, mitochondrial DNA (mtDNA) content was decreased. Moreover, copper/zinc superoxide dismutase (CuZn-SOD) expression at both mRNA and protein levels and SOD and catalase (CAT) activities were reduced in LE group as well.
The observed decrease in muscle mitochondrial biogenesis and antioxidant defense capacity suggests that moderately decreased maternal energy intake during pregnancy impairs mitochondrial function in fetal pigs.
Obesity, characterized by an imbalance between energy intake and expenditure, is increasing at an alarming rate in most parts of the world. In particular, human epidemiological and animal experimental studies have demonstrated that hormonal, metabolic, and nutritional disturbances at crucial prenatal time periods may also determine the predisposition to deleterious health outcomes in adult life, including obesity and associated metabolic disorders [3, 12, 20]. Thus, maternal undernutrition during pregnancy has been reported to have persistent effects on offspring metabolic energy regulatory systems [42, 45], although the underlying mechanisms of this process are still unclear.
Mitochondria are of major importance in oocyte and early embryo, playing a key role in maintaining energy homeostasis [26, 40]. Deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome, and many studies have demonstrated that prenatal maternal undernutrition programs offspring mitochondrial function in various tissues of different animal models, such as the pancreatic islet  and kidney  of rat and the skeletal muscle of sheep . The skeletal muscle composes about 40–50 % of body mass and is the major site of glucose and fatty acid utilization, playing an important role in preventing obesity and type 2 diabetes (T2D) [36, 47]. There is growing evidence that increased mitochondrial function may be essential for skeletal myogenesis . Moreover, mitochondrial dysfunction in the skeletal muscle is been implicated in the development of T2D [2, 19]. Studies in mice have shown that maternal exposure to a low-protein diet during pregnancy and lactation decreases mitochondrial DNA content and citrate synthase activity and leads to mitochondrial gene expression changes in the offspring liver and skeletal muscle [18, 27]. However, currently, to our knowledge, no studies have addressed the effects of maternal low-energy (LE) diets on fetal offspring skeletal muscle mitochondrial biogenesis and function.
Compared with sheep and rodents, pigs share a number of anatomical and physiological similarities with humans making them an excellent experimental model for metabolic studies [31, 39]. However, there is no data in the pig skeletal muscle on how maternal LE intake during pregnancy may affect mitochondrial number and function. In addition, prenatal skeletal muscle development is particularly susceptible to environmental factors in mammalians . Thus, understanding the effect of maternal LE diet on mitochondrial biogenesis and function in the skeletal muscle of the pig fetuses may provide important insights into the fetal origins of the metabolic syndrome. In the present study, our objective was to investigate the effects of moderately decreased maternal dietary energy intake during pregnancy on skeletal muscle mitochondrial biogenesis in pig fetuses on day 90 of pregnancy.
Animals and diets
Ingredients and composition of the experimental diets (as-fed basis)
Wheat bran fiber
L-Lys·HCl, 75 %
Choline chloride, 50 %
Digestible energy, MJ/kg
Crude protein (%)
Crude fiber (%)
Met + Cys (%)
Available P (%)
Total P (%)
After a 12-h overnight fast, pregnant sows of both groups (SE/LE) were weighed and anesthetized with an intramuscular injection of Zoletil (Zoletil 50, Virbac; 4 mg/kg body weight) on day 90 of pregnancy (n = 4/4). The maternal abdomen was opened, and the reproductive tracts were removed immediately. Blood from the umbilical vein of each fetus was collected and coagulated for 30 min and then centrifuged at 3500×g for 10 min to separate serum which was stored at −20 °C until analysis. The body weight of each fetus was recorded. Two female fetuses and two male fetuses, with weight close to the average level, were selected from each sow for muscle sample collection. The longissimus muscles (LMs) were collected from the fetuses, snap-frozen in liquid nitrogen, and stored at −80 °C until subsequent analysis.
Measurement of metabolites and hormone
The malondialdehyde (MDA) concentration in the skeletal muscle was measured using an assay kit (Jiancheng Institute of Bioengineering, Nanjing, Jiangsu, China). The concentrations of triglyceride and glucose in umbilical vein serum were determined using commercial kits (Jiancheng Institute of Bioengineering, Nanjing, Jiangsu, China) according to the provided instructions. Growth hormone (GH) concentration in umbilical vein serum was measured using a commercially available radioimmunoassay kits purchased from Beijing North Institute of Biotechnology (Beijing, China). Insulin was determined with porcine ELISA kit (R&D Systems, Minneapolis, MN, USA). Sensitivities of the assays were 0.02 ng/ml and 2.15 pmol/l for GH and insulin, respectively. Intra- and inter-assay coefficients of variation were 4.3 and 6.6 % for GH and 3.9 and 7.4 % for insulin, respectively.
Measurement of enzyme activities
The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the skeletal muscle were measured using assay kits (Jiancheng Institute of Bioengineering, Nanjing, Jiangsu, China). Citrate synthase (CS) activity in the skeletal muscle was measured spectrophotometrically using a commercial kit (GenMed Scientifics Inc, USA).
NAD+-to-NADH ratio measurement
The NAD+-to-NADH ratio in the skeletal muscle was measured using a colorimetric assay kit (BioVision, Milpitas, CA, USA) according to the manufacturer’s instructions. Briefly, muscle samples were washed with cold PBS followed homogenization using NAD+/NADH extraction buffer. To decompose NAD+, 200 μl of extract was heated to 60 °C for 30 min. Under this condition, all NAD+ were decomposed but keeping NADH intact. Both heated and unheated extract from each sample, together with the NADH standard solutions, were transferred into 96-well plates, added with 100 μl of NAD cycling mix into each well, mixed, and incubated at room temperature for 5 min to convert NAD+ to NADH. Then, 10 μl of NADH developer was added into each well and incubated at room temperature for 2 h. Read the plate at OD 450 nm. The amount of NAD+ from each sample was calculated as total NAD (values from the unheated extracts) minus NADH (values from the heated extracts) and then divided by the protein concentration.
Mitochondrial DNA copy number
Primer sequences of the target and reference genes
Primer sequence (5′–3′)
Product size (bp)
Liu et al. 
Liu et al. 
Liu et al. 
Quantitative real-time PCR
Total RNA was extracted from frozen muscle tissues using RNAiso Plus reagent (Takara, Dalian, China), and complementary DNA (cDNA) was synthesized from 0.5 μg of the total RNA using the PrimeScript™ RT reagent kit (Takara). Real-time quantitative PCR was carried out in the final volume of 10 ul containing 5 ul of SYBR® Premix Ex TaqTM II, 0.8 ul of the primer pair, 0.2 ul of ROX Reference Dye, 1 ul of cDNA template, and 3 ul of dH2O using the ABI Prism® 7900HT Sequence Detection System (Applied Biosystems, Foster city, CA, USA). The thermal cycling parameters comprised an initial denaturation step at 95 °C for 30 s, 40 cycles of PCR reaction at 95 °C for 5 s, and 60 °C for 34 s, followed by a dissociation step at 95 °C for 15 s, 60 °C for 1 min, and 95 °C for 15 s. To confirm specific product amplification, melt curve analysis was conducted. Primers for individual genes were designed using Primer Express 3.0 (Applied Biosystems) and are shown in Table 2. For normalization, ACTB was chosen as the reference gene since no variation in its expression was observed between treatments. The messenger RNA (mRNA) level of each target gene for SE group was set to 1.0.
Total protein was extracted from frozen muscle tissue using the protein extraction kit (Beyotime Biotechnology, Jiangsu, China) according to the manufacturer’s guide. The protein content of lysates was measured with the Pierce BCA protein Assay kit (Thermo, Waltham, MA, USA). Immunoblotting analysis was performed as previously described . The primary antibodies included PPARGC1A (ab54481, Abcam, Cambridge, MA, USA), Sirt1 (sc-19857, Santa Cruz Biotechnology, CA, USA), CuZn-SOD (sc-271014, Santa Cruz Biotechnology), and β-tubulin (sc-9104, Santa Cruz Biotechnology). The density of bands was quantified using the Gel Doc XR System (Bio-Rad, Hercules, CA, USA) and then normalized to β-tubulin content. The normalized values were used for comparison of the expression of target protein between SE and LE groups.
Results were presented as least square means with their standard errors. Data were analyzed using the MIXED procedures of Statistical Analysis System (version 8.1, SAS Institute, Inc.) with treatment, gender, and the two-way interactions as the fixed effect and with sow as the random effect. However, none of the gender and interactions were statistically significant. Therefore, they were removed from the model, and data from female and male fetuses were pooled together for analysis. The least square means were separated using the PDIFF option with the Turkey adjustment. The 2−ΔΔCt method was used to analyze the relative changes in each gene expression . Statistical significance was considered as P < 0.05, and a tendency towards difference was considered as P < 0.10.
Sow body weight, litter size, fetal weight, and variation in fetal weight within a litter on day 90 of pregnancy
Sow BW (kg)
At day 90 of pregnancy
Fetal weight (g)
Serum concentrations of metabolites and hormone
Concentrations of metabolites and hormones in fetal umbilical vein serum on day 90 of pregnancy
Mitochondrial DNA contents, CS activity, and the NAD+-to-NADH ratio
Expression of genes implicated in mitochondrial biogenesis and function
MDA level, CuZn-SOD gene expression, and antioxidant enzyme activities in the skeletal muscle
Malondialdehyde content and antioxidant enzyme activities in the fetal longissimus muscle of SE and LE sows
MDA (nmol/mg protein)
SOD (U/mg protein)
GPx (U/mg protein)
CAT (U/mg protein)
Epidemiological data demonstrate that low birth weight due to maternal malnutrition is associated with increased rates of metabolic diseases in adulthood [1, 11]. This study used the domestic pig as an animal model for the study of maternal nutrition and is of interest for human health and livestock science. Consistent with previous reports [15, 32], the maternal LE diets decreased fetal weight, which was linked to significantly lower serum GH concentration. Cumulative evidence have shown that mitochondrial dysfunction in the skeletal muscle is implicated in the developmental origins of metabolic syndrome [3, 43]. Mitochondria are inherited through the maternal lineage and easily affected by the environment because of its position outside the nucleus . It was reported that maternal low-protein diets during gestation affect mtDNA transcription regulation through changing the DNA methylation and hydroxymethylation on the promoter of mtDNA in the liver of newborn piglets . Previous studies in rodents also suggest that maternal nutritional stress causes changes to skeletal muscle mitochondrial function and oxidative metabolism that persist into adult offspring, increasing the risk of T2D [4, 21]. Moreover, because mitochondrial biogenesis accompanies skeletal myogenesis , and we previously reported that maternal LE diets attenuate fetal skeletal muscle development , thus, we hypothesized that the impairment of mitochondrial biogenesis may contribute to maternal LE diet-induced delayed skeletal myogenesis in pig fetuses. In the present study, we found that maternal LE diets during pregnancy decreased the mtDNA copy number in the skeletal muscle of LE fetuses, indicating a decrease in mitochondrial density. Similar results have been reported previously in rats’ offspring of dams fed with a low-protein diet [30, 41]. However, some studies have shown no consistent effects, and even advantageous effects, on mtDNA copy number when prenatal exposure to maternal low-protein diets in various tissues of different animal models, including the muscle in sheep  and muscle  and kidney  in rats, as well as fat in mice . Thus, there are contradictory results on how maternal nutritional limitation during pregnancy affects mitochondrial biogenesis in the offspring. These findings imply that the time period and duration of treatment during pregnancy, the type and amount of nutrient changes, and the different animal models and tissues tested seem to be important factors resulting in variation between studies. To our knowledge, this is the first report regarding the effect of maternal LE diets on mtDNA content in the skeletal muscle of pig fetuses.
The decrease in muscle mtDNA content indicates disrupted mitochondrial biogenesis. The control of mitochondrial biogenesis is a complex biological process that needs the coordinated regulation of multiple transcriptional factors, including nuclear and mitochondrial-encoded genes . It is well established that the NAD+-dependent deacetylase Sirt1 plays an important role in numerous fundamental cellular processes including gene silencing, DNA repair, and metabolic regulation . In our study, the expression of Sirt1 at both the mRNA and protein levels was reduced in the skeletal muscle of LE fetuses. Because Sirt1 deacetylase activity is driven by NAD+ levels, we examined whether maternal LE diets suppress Sirt1 by altering the intracellular NAD+/NADH ratio. Supporting this hypothesis, the NAD+/NADH ratio was decreased in LE fetuses. However, NADH content was not changed by maternal LE diets, implying that, apart from the interconversion of NAD+ and NADH during redox reactions, the concentration of both partners of this redox pair may be controlled by other mechanisms as well. Previous study in astrocytes has shown that both NAD+ and NADH contents are controlled independently from each other . Sirt1 deacetylates and activates PPARGC1A [10, 13], the master regulator of mitochondrial biogenesis that coactivates the NRF-1, which induce the expression of genes involved in mitochondrial biogenesis . In the present study, we found that the mRNA and protein expression of PPARGC1A were reduced in the skeletal muscle of LE fetuses. Consistently, the mRNA expression of NRF1 were decreased in LE fetuses. With further investigation, the mRNA expression of TFAM, a direct regulator of mtDNA replication and transcription that could be regulated by PPARGC1A and NRF1 , was reduced in LE fetuses as well. Similar with previous reports in rats [30, 41], abnormal expression patterns of genes implicated in mtDNA biogenesis in the offspring liver or pancreatic islets of malnourished dams were observed. Additionally, because ATP5B is a critical molecule required for mitochondrial ATP synthesis , the decrease of mitochondrial biogenesis in LE fetuses was also reflected by down-regulated expression of ATP5B. Gamma DNA polymerase (POLG) and SSBP1 play a key role in mtDNA replication and repair . As expected, we observed a decrease in POLG and SSBP1 in the skeletal muscle of LE fetuses. Together, these data show that maternal LE diets significantly reduced intracellular NAD+ levels and as a result decreased Sirt1 expression that subsequently decreased mtDNA replication and mitochondrial biogenesis in the skeletal muscle of LE fetuses.
Maternal malnutrition is associated with a depressed mitochondrial function and respiration in offspring [4, 9, 17]. In this study, although the mRNA expression levels of genes, such as COX4 and CYCS, responsible for mitochondrial function were not changed in LE fetuses, CS mRNA expression and activity were markedly decreased. Because it has been suggested a role for oxidative stress in skeletal muscle mitochondrial dysfunction , we speculate that oxidative stress may be implicated in undernutrition-associated mitochondrial alterations. ROS removal is regulated by many antioxidant enzymes, including SOD, GPx, and CAT . In the present study, the mRNA and protein expression of CuZn-SOD and activities of SOD and CAT were reduced in the skeletal muscle of LE fetuses, suggesting the failure of ROS defense system, which is also an evidence of mitochondrial function changes . However, muscle GPx activity was not changed by maternal LE diets. Thus, changes in the antioxidant system seem to occur in an enzyme-specific manner in prenatal energy-restricted fetal pigs. Similarly, previous study showed that maternal protein malnutrition significantly reduced SOD activity while GPx activity was not significantly affected in the liver of rat offspring . Therefore, the enhanced oxidative stress may not explain completely the mitochondrial changes in the fetal muscle as a whole. Previous studies have shown that acute GH action promotes muscle mitochondrial function by stimulating mitochondrial oxidative capacity and transcript abundance of mitochondrial genes . It is here shown that GH concentrations in umbilical vein serum of LE fetuses were reduced, which could, at least partly, explain the decreases in skeletal muscle mitochondrial biogenesis and function.
This study was supported by the National Basic Research Program of China (2012CB124701) and the National Natural Science Foundation of China (31372323).
TZ, BY, JY, XM, PZ, JH, and ZH participated in the design of the study and performed the statistical analysis. DC conceived and designed the study and helped in drafting the manuscript. TZ and YL carried out the animal experiments and performed the laboratory work. TZ wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
All institutional and national guidelines for the care and use of laboratory animals were followed. The experimental procedures were approved by the Animal Care and Use Committee of Sichuan Agricultural University.
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