Maternal Nutrient Restriction Confers Myocardial Remodeling in Association with Dampened Autophagy and Mitophagy in Adult Sheep Offspring

Jun, Ren

doi:10.53941/ijddp.2025.100003

Open Access

Article

Maternal Nutrient Restriction Confers Myocardial Remodeling in Association with Dampened Autophagy and Mitophagy in Adult Sheep Offspring

Wei Ge¹

,

Qiurong Wang^{2, 3}

,

Jun Tao⁴

,

Stephen P. Ford^{5, †}

,

Wei Guo^{6, 7}

,

Xiaoming Wang^{8, *}

,

Jun Ren^{2, 3, *}

Author Information

Submitted: 19 Oct 2023 | Revised: 23 Nov 2023 | Accepted: 24 Nov 2024 | Published: 13 Feb 2025

Abstract

The “thrifty phenotype” resulted from maternal malnutrition is considered a vital predisposing factor for the etiology of metabolic anomalies in offspring. To unveil the underlying mechanisms of heart diseases consequential to maternal malnutrition, pregnant ewes were kept on a nutrient restricted (NR: 50%) or control diet (100%) from day 28 to 78 of gestation. The experimental diet was then switched to a normal nutrition diet regimen till lambing. At 6 years of age, cardiac structure and function were evaluated following a 12-week palatable diet in adult offspring from control and maternal NR groups, along with insulin signaling, autophagy, mitophagy and pro-inflammatory cytokines. Our results revealed that offspring from NR ewes displayed greater body, heart, and ventricular weights along with cardiomyocyte mechanical anomalies (poor cell shortening capacity, prolonged relengthening and intracellular Ca²⁺ clearance with a pronounced response in left ventricles), cardiac remodeling (enlarged cardiomyocyte size and interstitial fibrosis) and O₂^- accumulation. Proinflammatory cytokines including TLR4, TNFα and IL1β were upregulated in right ventricles along with higher STAT3 in left ventricles with little changes in GLUT4 following maternal NR. Levels of autophagy and mitophagy were downregulated in both ventricles from NR offspring (LC3BII, Atg7, Parkin, FUNDC1 and BNIP3 with higher p62 and unchanged Beclin1). Maternal nutrient restriction also promoted serine phosphorylation of IRS1 and suppressed AMPK phosphorylation without affecting Akt phosphorylation in both ventricles. Phosphorylation of mTOR was elevated in left but not right ventricles from NR offspring. These findings collectively unveiled a predisposing role of maternal malnutrition in cardiac anomalies in adulthood, possibly related to regulation of phosphorylation of IRS1 and AMPK, proinflammatory cytokines, autophagy and mitophagy. Targeting autophagy/mitophagy, IRS1 and AMPK such as using metformin and HM-chromanone may hold therapeutic promises in NR offspring with cardiac conditions.

Keywords

References

1.

Fan, X.; Turdi, S.; Ford, S.P.; et al. Influence of gestational overfeeding on cardiac morphometry and hypertrophic protein markers in fetal sheep. J. Nutr. Biochem. 2011, 22, 30–37.

2.

Wang, L.; O'Kane, A.M.; Zhang, Y.; et al. Maternal obesity and offspring health: Adapting metabolic changes through autophagy and mitophagy. Obes. Rev. 2023, 24, e13567.

3.

Wang, J.; Ma, H.; Tong, C.; et al. Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart. FASEB J. 2010, 24, 2066–2076.

4.

Dong, F.; Ford, S.P.; Nijland, M.J.; et al. Influence of maternal undernutrition and overfeeding on cardiac ciliary neurotrophic factor receptor and ventricular size in fetal sheep. J. Nutr. Biochem. 2008, 19, 409–414.

5.

Kandadi, M.R.; Hua, Y.; Zhu, M.; et al. Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart. J. Nutr. Biochem. 2013, 24, 1982–1990.

6.

Diniz, M.S.; Grilo, L.F.; Tocantins, C.; et al. Made in the Womb: Maternal Programming of Offspring Cardiovascular Function by an Obesogenic Womb. Metabolites 2023, 13, 845.

7.

Zambrano, E.; Lomas-Soria, C.; Nathanielsz, P.W. Rodent studies of developmental programming and ageing mechanisms: Special issue: In utero and early life programming of ageing and disease. Eur. J. Clin. Investig. 2021, 51, e13631.

8.

Roberts, J.M.; Heider, D.; Bergman, L.; et al. Vision for Improving Pregnancy Health: Innovation and the Future of Pregnancy Research. Reprod. Sci. 2022, 29, 2908–2920.

9.

Huber, H.F.; Jenkins, S.L.; Li, C.; et al. Strength of nonhuman primate studies of developmental programming: Review of sample sizes, challenges, and steps for future work. J. Dev. Orig. Health Dis. 2020, 11, 297–306.

10.

Bar, J.; Weiner, E.; Levy, M.; et al. The thrifty phenotype hypothesis: The association between ultrasound and Doppler studies in fetal growth restriction and the development of adult disease. Am. J. Obstet. Gynecol. MFM 2021, 3, 100473.

11.

Vaag, A.A.; Grunnet, L.G.; et al. The thrifty phenotype hypothesis revisited. Diabetologia 2012, 55, 2085–2088.

12.

Hales, C.N.; Barker, D.J. The thrifty phenotype hypothesis. Br. Med. Bull. 2001, 60, 5–20.

13.

Godfrey, K.; Robinson, S. Maternal nutrition, placental growth and fetal programming. Proc. Nutr. Soc. 1998, 57, 105–111.

14.

Dong, M.; Zheng, Q.; Ford, S.P.; et al. Maternal obesity, lipotoxicity and cardiovascular diseases in offspring. J. Mol. Cell Cardiol. 2013, 55, 111–116.

15.

Barker, D.J. Coronary heart disease: A disorder of growth. Horm. Res. 2003, 59 (Suppl. 1), 35–41.

16.

Barker, D.J.; Gelow, J.; Thornburg, K.; et al. The early origins of chronic heart failure: Impaired placental growth and initiation of insulin resistance in childhood. Eur. J. Heart Fail. 2010, 12, 819–825.

17.

Gupta, M.B.; Jansson, T. Novel roles of mechanistic target of rapamycin signaling in regulating fetal growthdagger. Biol. Reprod. 2019, 100, 872–884.

18.

Green, A.S.; Rozance, P.J.; Limesand, S.W. Consequences of a compromised intrauterine environment on islet function. J. Endocrinol. 2010, 205, 211–224.

19.

Dong, F.; Ford, S.P.; Fang, C.X.; et al. Maternal nutrient restriction during early to mid gestation up-regulates cardiac insulin-like growth factor (IGF) receptors associated with enlarged ventricular size in fetal sheep. Growth Horm. IGF Res. 2005, 15, 291–299.

20.

Tarry-Adkins, J.L.; Aiken, C.E.; Ashmore, T.J.; et al. Insulin-signalling dysregulation and inflammation is programmed trans-generationally in a female rat model of poor maternal nutrition. Sci. Rep. 2018, 8, 4014.

21.

Tarry-Adkins, J.L.; Fernandez-Twinn, D.S.; Madsen, R.; et al. Coenzyme Q10 Prevents Insulin Signaling Dysregulation and Inflammation Prior to Development of Insulin Resistance in Male Offspring of a Rat Model of Poor Maternal Nutrition and Accelerated Postnatal Growth. Endocrinology 2015, 156, 3528–3537.

22.

Ren, J.; Anversa, P. The insulin-like growth factor I system: Physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome. Biochem. Pharmacol. 2015, 93, 409–417.

23.

Ajoolabady, A.; Chiong, M.; Lavandero, S.; et al. Mitophagy in cardiovascular diseases: Molecular mechanisms, pathogenesis, and treatment. Trends Mol. Med. 2022, 28, 836–849.

24.

Zhang, Y.; Whaley-Connell, A.T.; Sowers, J.R.; et al. Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management. Pharmacol. Ther. 2018, 191, 1–22.

25.

Han, H.C.; Austin, K.J.; Nathanielsz, P.W.; et al. Maternal nutrient restriction alters gene expression in the ovine fetal heart. J. Physiol. 2004, 558, 111–121.

26.

George, L.A.; Zhang, L.; Tuersunjiang, N.; et al. Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 302, R795–R804.

27.

Peng, H.; Zhang, J.; Zhang, Z.; et al. Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced cardiac anomalies through reconciliation of autophagy and ferroptosis. Life Sci. 2023, 328, 121821.

28.

Li, Q.; Wu, S.; Li, S.Y.; et al. Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am. J. Physiol. Heart Circ. Physiol. 2007, 292, H1398–H1403.

29.

Ren, J.; Wold, L.E. Measurement of Cardiac Mechanical Function in Isolated Ventricular Myocytes from Rats and Mice by Computerized Video-Based Imaging. Biol. Proced. Online 2001, 3, 43–53.

30.

Wang, Q.; Zhu, C.; Sun, M.; et al. Maternal obesity impairs fetal cardiomyocyte contractile function in sheep. FASEB J. 2019, 33, 2587–2598.

31.

Doser, T.A.; Turdi, S.; Thomas, D.P.; et al. Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction. Circulation 2009, 119, 1941–1949.

32.

Ge, W.; Hu, N.; George, L.A.; et al. Maternal nutrient restriction predisposes ventricular remodeling in adult sheep offspring. J. Nutr. Biochem. 2013, 24, 1258–1265.

33.

Sun, A.; Cheng, Y.; Zhang, Y.; et al. Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy. J. Mol. Cell Cardiol. 2014, 71, 92–104.

34.

Turdi, S.; Han, X.; Huff, A.F.; et al. Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: Role of autophagy. Free Radic. Biol. Med. 2012, 53, 1327–1338.

35.

Ma, H.; Li, J.; Gao, F.; et al. Aldehyde dehydrogenase 2 ameliorates acute cardiac toxicity of ethanol: Role of protein phosphatase and forkhead transcription factor. J. Am. Coll. Cardiol. 2009, 54, 2187–2196.

36.

Masoumy, E.P.; Sawyer, A.A.; Sharma, S.; et al. The lifelong impact of fetal growth restriction on cardiac development. Pediatr. Res. 2018, 84, 537–544.

37.

Harvey, T.J.; Murphy, R.M.; Morrison, J.L.; et al. Maternal Nutrient Restriction Alters Ca2+ Handling Properties and Contractile Function of Isolated Left Ventricle Bundles in Male But Not Female Juvenile Rats. PLoS ONE 2015, 10, e0138388.

38.

Molaei, A.; Molaei, E.; Hayes, A.W.; et al. Mas receptor: A potential strategy in the management of ischemic cardiovascular diseases. Cell Cycle 2023, 22, 1654–1674.

39.

Lillo, R.; Graziani, F.; Franceschi, F.; et al. Inflammation across the spectrum of hypertrophic cardiac phenotypes. Heart Fail. Rev. 2023, 28, 1065–1075.

40.

Sriramula, S.; Haque, M.; Majid, D.S.; et al. Involvement of tumor necrosis factor-alpha in angiotensin II-mediated effects on salt appetite, hypertension, and cardiac hypertrophy. Hypertension 2008, 51, 1345–1351.

41.

Copps, K.D.; Hancer, N.J.; Opare-Ado, L.; et al. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab. 2010, 11, 84–92.

42.

Sanz, R.L.; Inserra, F.; Garcia Menendez, S.; et al. Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins. Curr. Hypertens. Rep. 2023, 25, 91–106.

43.

Shao, J.; Yamashita, H.; Qiao, L.; et al. Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. Diabetes 2002, 51, 19–29.

44.

Shao, J.; Catalano, P.M.; Yamashita, H.; et al. Decreased insulin receptor tyrosine kinase activity plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): Evidence for increased serine/threonine phosphorylation in pregnancy and GDM. Diabetes 2000, 49, 603–610.

45.

Nair, S.; Ren, J. Autophagy and cardiovascular aging: Lesson learned from rapamycin. Cell Cycle 2012, 11, 2092–2099.

46.

Ren, J.; Wu, N.N.; Wang, S.; et al. Obesity cardiomyopathy: Evidence, mechanisms, and therapeutic implications. Physiol. Rev. 2021, 101, 1745–1807.

47.

Rouschop, S.H.; Snow, S.J.; Kodavanti, U.P.; et al. Perinatal High-Fat Diet Influences Ozone-Induced Responses on Pulmonary Oxidant Status and the Molecular Control of Mitophagy in Female Rat Offspring. Int. J. Mol. Sci. 2021, 22, 7551.

48.

Nathanielsz, P.W. A time to be born: Implications of animal studies in maternal-fetal medicine. Birth 1994, 21, 163–169.

49.

Milani-Nejad, N.; Janssen, P.M. Small and large animal models in cardiac contraction research: Advantages and disadvantages. Pharmacol. Ther. 2014, 141, 235–249.

50.

Davidoff, A.J.; Ren, J. Low insulin and high glucose induce abnormal relaxation in cultured adult rat ventricular myocytes. Am. J. Physiol. 1997, 272, H159–H167.

51.

Park, J.E.; Kang, E.; Han, J.S. HM-chromanone attenuates TNF-alpha-mediated inflammation and insulin resistance by controlling JNK activation and NF-kappaB pathway in 3T3-L1 adipocytes. Eur. J. Pharmacol. 2022, 921, 174884.

52.

Jacob Berger, A.; Gigi, E.; Kupershmidt, L.; et al. IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy. Nat. Cancer 2021, 2, 1055–1070.

53.

Huang, S.L.; Xie, W.; Ye, Y.L.; et al. Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice. Acta Pharmacol. Sin. 2023, 44, 596–609.

54.

Moll, L.; Ben-Gedalya, T.; Reuveni, H.; et al. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. FASEB J. 2016, 30, 1656–1669.

55.

Garcia-Contreras, C.; Vazquez-Gomez, M.; Pesantez-Pacheco, J.L.; et al. Maternal Metformin Treatment Improves Developmental and Metabolic Traits of IUGR Fetuses. Biomolecules 2019, 9, 166.

56.

Gatford, K.L.; Houda, C.M.; Lu, Z.X.; et al. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: Responses to maternal metformin compared with insulin treatment. Diabetes Obes. Metab. 2013, 15, 660–667.

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DOI

10.53941/ijddp.2025.100003

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Volume 4, Issue 1

How to Cite

Ge, W., Wang, Q., Tao, J., Ford, S. P., Guo, W., Wang, X., & Ren, J. (2025). Maternal Nutrient Restriction Confers Myocardial Remodeling in Association with Dampened Autophagy and Mitophagy in Adult Sheep Offspring. International Journal of Drug Discovery and Pharmacology, 4(1), 100003. https://doi.org/10.53941/ijddp.2025.100003

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