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

Article Maternal Nutrient Restriction Confers Myocardial Remodeling in Association with Dampened Autophagy and Mitophagy in Adult Sheep Offspring Wei Ge 1, Qiurong Wang 2,3, Jun Tao 4, Stephen P. Ford 5,†, Wei Guo 6,7, Xiaoming Wang 8,* and Jun Ren 2,3,* 1 Department of General Practice, Xijing Hospital, Air Force Medical University, Xi’an 710032, China 2 Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China 3 National Clinical Research Center for Interventional Medicine, Shanghai 200032, China 4 Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000, China 5 Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY 82071, USA 6 Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA 7 Cardiovascular Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA 8 Department of Geriatrics, Xijing Hospital, Air Force Medical University, Xi’an 710032, China * Correspondence: [email protected] (X.W.); [email protected] (J.R.) † Deceased. Received: 19 October 2023; Revised: 23 November 2023; Accepted: 24 November 2023; Published: 13 February 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.