Citrate Synthase Insufficiency Leads to Specific Metabolic Adaptations in the Heart and Skeletal Muscles Upon Low-Carbohydrate Diet Feeding in Mice

Abstract

A decrease in TCA cycle activity may lead to impaired nutrition metabolism and cellular energy shortage. Herein, we aimed to characterize the detailed metabolic changes that compensate for energy shortages in energy-consuming organs (heart and skeletal muscles) in mice with knockout of citrate synthase (CS), an important enzyme in the TCA cycle. CS hetero knockout (CS +/−) mice and wild-type mice were fed a low-carbohydrate ketogenic diet (LCKD) or high-fat, high-carbohydrate diet (HFHCD) to induce metabolic changes. Body weight, blood serum parameters, metabolic gene expression, and adenosine triphosphate (ATP) levels were measured in the heart and skeletal muscles. Glycogen content, anabolic and catabolic biomarkers, and morphological changes were also assessed in the skeletal muscles. After diet feeding, there were no differences observed in the body weight and blood serum parameters between wild-type and CS +/− mice. The cardiac expression of genes related to the utilization of fatty acids, monocarboxylates, and branched amino acids increased in LCKD-fed CS +/− mice. In contrast, no significant differences in gene expression were observed in the muscles of LCKD-fed mice or the heart and muscles of HFHCD-fed mice. ATP levels decreased only in the skeletal muscles of LCKD-fed CS +/− mice. Additionally, the decrease in glycogen content, suppression of p70 S6 kinase, and presence of type I fiber atrophy were observed in the muscles of LCKD-fed CS +/− mice. These results suggest that the energy-consuming organs with CS insufficiency may undergo tissue-specific adaption to compensate for energy shortages when the carbohydrate supply is limited.

Microbial Indoles: Key Regulators of Organ Growth and Metabolic Function

“…Interestingly, metabolic alterations (including reduced levels of glycogen and increased expression of genes that promote mitochondrial OXPHOS) in the CS knock-down mouse model only occurred under fasting-mimic conditions [50]. The fact that our MT mice experienced fasting-mimic conditions (upregulated lipid cycling, downregulated lipogenesis and Glu4 expression) is consistent with the phenomena of mild insulin resistance [51].…”

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats

“…Citrate synthase is the initial enzyme of the Krebs cycle and is important in the production of energy via mitochondrial respiration (i.e., oxidative phosphorylation) [ 121 ]. The enzyme is considered a biomarker for cellular oxidative capacity and mitochondrial content in striated muscle following a training regimen [ 37 , 122 , 123 ]. In this study, we observed an increased citrate synthase activity in LV tissue following MIT and HIIT.…”

Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice

“…Additionally, PD is associated with acetyl-CoA synthesis and TCA cycle dysfunction. When combined with respiratory chain dysfunction, this can exacerbate bioenergetic deficits [ 59 , 60 , 61 , 62 , 63 ].…”