Multi‐Omics Revealed the Effects of Intrauterine Hyperglycemia Exposure on the Development of Skeletal Muscle in Offspring

TL;DR

Exposure to high blood sugar in the womb harms offspring's muscle development, but exercise after birth can help reverse some of these effects.

Contribution

This study reveals how intrauterine hyperglycemia affects skeletal muscle development and shows that postnatal exercise can mitigate some of these effects.

Findings

IUHG leads to increased body weight, impaired glucose and insulin tolerance, and reduced muscle strength in offspring.

Postnatal exercise improves muscle structure, lipid profiles, and metabolic function in GDM-exposed offspring.

Transcriptomic and epigenomic changes in skeletal muscle include altered immune regulation, myogenesis, and lipid metabolism.

Abstract

Gestational diabetes mellitus (GDM), a common pregnancy complication characterized by maternal hyperglycemia, negatively impacts offspring health. Skeletal muscle, a critical tissue for glucose and lipid metabolism, is especially vulnerable to prenatal environmental insults. However, the effects of intrauterine hyperglycemia (IUHG) on offspring skeletal muscle development remain poorly understood. This study aimed to investigate the effects of IUHG on skeletal muscle development in offspring and evaluate whether postnatal exercise could mitigate these effects.

Pregnant mice were assigned to GDM and control groups. Offspring were further divided into control and exercise subgroups. Body weight, glucose tolerance test (GTT), insulin tolerance test (ITT), body composition, muscle strength and exercise capacity were assessed. At 20 weeks of age, skeletal muscle morphology was evaluated via various staining and Transmission Electron Microscope. Transcriptomic changes were analysed by RNA sequencing (RNA‐seq) and chromatin accessibility was assessed using ATAC‐seq to identify molecular mechanisms underlying IUHG‐induced alterations. Additionally, primary fetal myoblasts were cultured under normal and high‐glucose conditions to investigate metabolic changes and lipid accumulation in vitro.

Offspring exposed to IUHG exhibited increased body weight, impaired glucose and insulin tolerance, altered body composition, reduced muscle strength and diminished exercise capacity at adulthood. Exercise intervention in diabetic offspring improved the muscle ratio (p < 0.05), fat ratio (p < 0.05), lipid profiles (p < 0.005) and muscle structure and strength (p < 0.005). Transcriptomic and epigenomic profiling identified significant changes in genes and regulatory elements associated with immune regulation, myogenesis, lipid metabolism and inflammation in GDM‐exposed offspring. In vitro, high‐glucose exposure of E14.5d fetal myoblasts led to significant metabolic reprogramming, including lipid accumulation and disruptions in glycolysis and oxidative metabolism. Furthermore, the expression of AP‐1 family members Fos and Junb was up‐regulated in myoblasts under high‐glucose conditions, which aligns with the findings in the in vivo models.

IUHG disrupts skeletal muscle development and metabolic function in offspring through structural, transcriptional and epigenetic alterations. Postnatal exercise partially reversed these impairments, highlighting its potential as a non‐pharmacological intervention. These findings provide new insights into the developmental origins of skeletal muscle dysfunction in GDM‐exposed offspring and underscore the importance of early prevention strategies.

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