Prenatal Low-Protein Diet Affects Mitochondrial Structure and Function in the Skeletal Muscle of Adult Female Offspring

Abstract

Gestational low-protein (LP) diet leads to glucose intolerance and insulin resistance in adult offspring. We had earlier demonstrated that LP programming affects glucose disposal in females. Mitochondrial health is crucial for normal glucose metabolism in skeletal muscle. In this study, we sought to analyze mitochondrial structure, function, and associated genes in skeletal muscles to explore the molecular mechanism of insulin resistance LP-programmed female offspring. On day four of pregnancy, rats were assigned to a control diet containing 20% protein or an isocaloric 6% protein-containing diet. Standard laboratory diet was given to the dams after delivery until the end of weaning and to pups after weaning. Gestational LP diet led to changes in mitochondrial ultrastructure in the gastrocnemius muscles, including a nine-fold increase in the presence of giant mitochondria along with unevenly formed cristae. Further, functional analysis showed that LP programming caused impaired mitochondrial functions. Although the mitochondrial copy number did not show significant changes, key genes involved in mitochondrial structure and function such as Fis1, Opa1, Mfn2, Nrf1, Nrf2, Pgc1b, Cox4b, Esrra, and Vdac were dysregulated. Our study shows that prenatal LP programming induced disruption in mitochondrial ultrastructure and function in the skeletal muscle of female offspring.

Maternal diet induces persistent DNA methylation changes in the muscle of beef calves

“…Some of the genes that showed persistent DNA methylation changes are closely related to mitochondrial function, reactive oxygen species (ROS) metabolic process, and redox regulation. These results are in concordance with previous studies that have shown that maternal nutrition during gestation can significantly alter muscle mitochondrial function and ROS homeostasis in the offspring 32 – 34 . Note that mitochondria are key organelles involved in generating ATP via oxidative phosphorylation, but apart from this main role, mitochondria also have other functions, including apoptosis regulation, calcium homeostasis, and ROS production 35 .…”

Low Protein Programming Causes Increased Mitochondrial Fusion and Decreased Oxygen Consumption in the Hepatocytes of Female Rats

“…Therefore, we think mitochondrial dysfunction is more widespread and affects both the liver and skeletal muscle. Interestingly, the LP diet did not change the hepatic mitochondrial copy number, similar to our observations in skeletal muscles [ 5 ]. Our present observations indicate that the mitochondrial dysfunction seen in the hepatocytes might be due to the abundance of dysfunctional mitochondria rather than the difference in the total mitochondrial number.…”

“…However, the molecular mechanisms leading to unregulated glucose metabolism are not well studied. Recently, we reported the presence of hyper fused and dysfunctional mitochondria in the LP-programmed female skeletal muscle, as well as its role in the development of insulin resistance and lean T2D [ 5 ]. Similarly, in the present study, we found a higher number of fused mitochondria in the LP group.…”

“…Similarly, other studies have shown that an in utero LP diet can lead to mitochondrial dysfunction in offspring [ 30 , 35 , 36 ]. Our recent study in the skeletal muscle showed reduced maximal respiration-linked OCR [ 5 ]. Therefore, we think mitochondrial dysfunction is more widespread and affects both the liver and skeletal muscle.…”

“…Hepatic mitochondria play a central role in glucose metabolism, and the presence of defective mitochondria in the liver and skeletal muscle is often attributed to the origin of insulin resistance [ 4 ]. We previously reported that a prenatal LP diet leads to mitochondrial dysfunction in the skeletal muscles of adult offspring [ 5 ]. However, the impact of LP programming on hepatic mitochondria is not clearly understood and is the subject of our present study.…”