Pregnancy-induced metabolic reprogramming in skeletal muscle: a multi-omics interrogation of transcriptional and metabolic adaptations

Abstract

Pregnancy induces profound physiological adaptations to meet the dynamic nutritional demands of fetal development, including a deliberate reduction in maternal insulin sensitivity to ensure fetal glucose availability. However, excessive insulin resistance may precipitate gestational diabetes mellitus (GDM), increasing the risk of both obstetric complications and long-term metabolic disorders in mothers and offspring. Although the role of adipose tissue in pregnancy-associated metabolic adaptation has been extensively studied, the contribution of skeletal muscle remains poorly understood. Here, we systematically characterize pregnancy-induced molecular and metabolic changes in maternal skeletal muscle through multi-omics profiling. We use transcriptomic, metabolomic, computational single-cell deconvolution, and qPCR validation in an established C57BL/6J mouse pregnancy model (8-week-old females). Pregnancy triggers remarkable skeletal muscle remodelling, featuring histological reorganization with myofiber depletion and expanded endothelial compartments. Concurrent metabolic disturbances include insulin resistance, dysregulated TCA cycle activity, and impaired ubiquinone biosynthesis. This study represents a multi-omics-based systematic elucidation of pregnancy-induced maternal skeletal muscle adaptations. Our findings demonstrate that pregnancy induces profound structural reorganization and metabolic reprogramming in maternal skeletal muscle, characterized by prioritized fetal nutrient provision at the expense of maternal tissue utilization. These observations not only reveal previously unrecognized mechanisms of pregnancy-specific metabolic regulation but also, more importantly, establish a critical theoretical foundation for developing skeletal muscle-targeted intervention strategies to prevent gestational diabetes mellitus.

1. Introduction

Gestational diabetes mellitus (GDM) has emerged as a major global health challenge, with prevalence rates increasing to 2%–25% across populations worldwide [1]. Defined by the new onset of glucose intolerance, GDM encompasses conditions ranging from newly detected hyperglycemia during pregnancy to pre-existing impaired glucose tolerance or overt type 2 diabetes mellitus (T2DM). This condition has profound clinical implications: longitudinal studies have revealed that nearly 50% of GDM women develop T2DM within five years post-partum, whereas their offspring face significantly increased risks of obesity and metabolic syndrome [2,3]. This transgenerational metabolic programming underscores GDM’s critical role in the developmental origins of metabolic disorders, highlighting the urgent need to decipher its underlying mechanisms.

The metabolic adaptations of pregnancy, while physiologically necessary to support fetal growth, create a precarious balance that may predispose individuals to GDM. The current understanding emphasizes adipose tissue expansion as the primary driver of pregnancy-induced insulin resistance, accounting for approximately one-third of the recommended gestational weight gain [4–7]. However, emerging evidence indicates that among insulin-responsive tissues, skeletal muscle—more prominently than hepatic tissue—undergoes pregnancy-specific suppression of insulin signaling pathways, in addition to adipose tissue involvement [8]. These findings position skeletal muscle as a potentially crucial mediator of gestational metabolic reprogramming, suggesting that its maladaptation may be instrumental in GDM pathogenesis.

The parallels between GDM and T2DM pathophysiology further reinforce the likely contribution of skeletal muscle [9]. As the tissue responsible for the majority of insulin-stimulated glucose disposal, skeletal muscle is recognized as the primary site of insulin resistance in T2DM patients. Emerging data indicate similar centrality in GDM, where pregnancy-induced skeletal muscle metabolic derangements strongly correlate significantly positively with insulin resistance severity and independently predict GDM risk. This association may be mediated through impaired insulin signal transduction in skeletal muscle [10], mitochondrial dysfunction-induced metabolic inflexibility [11,12], and myokine-mediated systemic inflammation [13,14]. Despite these advances, the molecular mechanisms underlying pregnancy-specific skeletal muscle metabolic remodelling and its causal re