PSV-3 Effects of maternal early gestational weight gain on multigenerational skeletal muscle gene regulation in offspring

Abstract

Abstract Maternal nutrition during the periconceptional period may have multigenerational effects on the gene regulation of fetal skeletal muscle. This study aimed to investigate the impact of maternal rate of body weight gain (F0) during early gestation on the differential gene expression in the skeletal muscle of newborn (F1) and second-generation fetuses (F2) female offspring. To this end, crossbred Angus heifers (F0) were assigned to either a low gain (LG; 0.28 kg/d; n = 8) or moderate gain (MG; 0.79 kg/d; n = 8) group during the first 84 d of gestation. Subsequently, heifers (F0) were managed as a single group on a forage-based diet until the weaning of the F1 offspring (8 mo). The F1 heifers were estrus synchronized and bred via AI at 15 mo, and F2 fetuses were harvested on d 84 of gestation. Longissimus dorsi muscle was collected at birth (F1) and the 84-d harvest in F1 heifers and their F2 fetuses for multigenerational RNA-Seq analysis. Differentially expressed genes (DEGs) were identified using the DESeq2 R-package. Significant genes were retrieved based on P - value ≤ 0.05 and log2 fold change|0.5|. We previously reported that F1 heifers from MG dams at birth were ~2 kg heavier (P < 0.03), and herein we report the impact on the gene regulation of skeletal muscle in the F1 and F2 generations. At birth, F1 heifers from MG cows exhibited 275 DEGs, of which 98 were downregulated, and 177 genes were upregulated, related to the immune system (TNFAIP3, TLR5), cellular signaling and transduction (RASGRP2, NFE2), and extracellular matrix (TGM3, MMP17). Changes in gene expression persisted in F1 heifers through development, breeding, and until the evaluation at d 84 of gestation. At this time point, we identified 75 upregulated genes out of 177 DEGs. These genes were underlying cellular functions (USP43, PASK), hematopoiesis (THPO), metabolism, and enzymatic activity (SMOX, OAT) as possible metabolic adaptations. Similarly, 102 genes were downregulated, mainly associated with immune and inflammatory response (CHI3L1, LDAF1). Regarding the F2 fetuses, 151 DEGs were differentially expressed. Among them, 63 were upregulated in the MG group and involved with biological functions such as ion channels and transport (KCNAB1, SLC9A3), transcriptional regulation, and signaling (ZNF75D, TMEM106B, DPP6), enzymatic activity, and metabolism (B3GNT4, FAM20A, ALDH5A1, and PRSS23). Likewise, 88 downregulated genes were associated with the cell cycle and proliferation (APOOL, CIR1, and STIL). In conclusion, periconceptional maternal nutrition aimed at moderate weight gains can have multigenerational effects on the gene regulation of fetal muscle tissue.