Cardiomyocyte Pdk4 response is associated with metabolic maladaptation in aging

Abstract

Ischemic heart disease (IHD) is the leading cause of death, with age range being the primary factor for development. The mechanisms by which aging increases vulnerability to ischemic insult are not well understood. We aim to use single‐cell RNA sequencing to discover transcriptional differences in various cell types between aged and young mice, which may contribute to aged‐related vulnerability to ischemic insult. Utilizing 10× Genomics Single‐Cell RNA sequencing, we were able to complete bioinformatic analysis to identity novel differential gene expression. During the analysis of our collected samples, we detected Pyruvate Dehydrogenase Kinase 4 (Pdk4) expression to be remarkably differentially expressed. Particularly in cardiomyocyte cell populations, Pdk4 was found to be significantly upregulated in the young mouse population compared to the aged mice under ischemic/reperfusion conditions. Pdk4 is responsible for inhibiting the enzyme pyruvate dehydrogenase, resulting in the regulation of glucose metabolism. Due to decreased Pdk4 expression in aged cardiomyocytes, there may be an increased reliance on glucose oxidization for energy. Through biochemical metabolomics analysis, it was observed that there is a greater abundance of pyruvate in young hearts in contrast to their aged counterparts, indicating less glycolytic activity. We believe that Pdk4 response provides valuable insight towards mechanisms that allow for the young heart to handle ischemic insult stress more effectively than the aged heart.

PDK4 rescues high-glucose-induced senescent fibroblasts and promotes diabetic wound healing through enhancing glycolysis and regulating YAP and JNK pathway

“…Our findings confirm that PDK4 can effectively ameliorate the senescence phenotype in fibroblasts induced by high glucose. Notably, these observations are consistent with previous reports suggesting a role for PDK4 in the regulation of cellular senescence [10,11,13,14]. Moreover, overexpression of PDK4 accelerated wound healing in diabetic mice, decreased the expression of senescence markers in wound tissue, and promoted collagen deposition.…”

“…Recent studies have demonstrated that PDK4 is also involved in regulating cellular senescence phenotypes. Reduced PDK4 expression has been observed in aging cardiomyocytes, which is associated with metabolic maladaptation [10,11]. Besides, putrescine delays postovulatory aging of mouse oocytes by upregulating PDK4 expression and improving mitochondrial activity [12].…”

Construction and analysis of a network of exercise-induced mitochondria-related non-coding RNA in the regulation of diabetic cardiomyopathy

“…PDK4 is a key regulator of glucose metabolism, fatty acid oxidation, and oxidation-reduction. It was found PDK4 expression plays a key role in regulating glucose metabolism in aging and therefore mediating cardiomyocyte injury in ischemia reperfusion and aging [ 44 , 45 ]. PDK4 is largely responsible for inhibiting pyruvate dehydrogenase (PDH) in the presence of fatty acids and increasing the reliance of the heart on fatty acid oxidation for energy production [ 46 , 47 ].…”

Roles of the crucial mitochondrial DNA in hypertrophic cardiomyopathy prognosis and diagnosis: A review

“…PDK4 plays a role in regulating mitochondrial dynamics, which can prevent diastolic dysfunction. [ 29 ] PDK4 upregulation is associated with mitochondrial damage by affecting the status of cellular respiratory system. [ 30 ] Mitochondrial dysfunction is a common pathogenic mechanism in patients with HCM, suggesting that it may be important in the pathogenesis of HCM.…”