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

Abstract

During the process of wound healing, fibroblasts migrate to the wound site and perform essential functions in promoting cell proliferation, as well as synthesizing and secreting the extracellular matrix (ECM). However, in diabetic wounds, senescent fibroblasts exhibit impaired proliferative capacity and fail to synthesize essential ECM components. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating cellular senescence and fibroblast function. However, its specific role in diabetic wounds remains poorly understood. In this study, we conducted a series of in vivo and in vitro experiments using STZ-induced diabetic mice and human dermal fibroblasts. We evaluated cellular senescence markers, including SA-β-gal, P53, P16, P21, and PAI-1, as well as senescence-associated secretory phenotype (SASP) factors. Finally, we observed that PDK4 increased in normal wound healing, but its expression was insufficient in diabetic wounds. Significantly, the overexpression of PDK4 demonstrated the potential to accelerate diabetic wound healing and improve the senescence phenotype both in vivo and in vitro. Furthermore, our study elucidated the underlying mechanism by which PDK4 improved the senescent phenotype through the enhancement of glycolysis and regulation of YAP and JNK pathway. The effect was dependent on metabolic reprogramming and subsequent reduction of reactive oxygen species (ROS), which was mediated by PDK4. Overall, our findings highlight the potential of PDK4 as a promising therapeutic target for addressing diabetic wounds.

Selenium Compounds Affect Differently the Cytoplasmic Thiol/Disulfide State in Dermic Fibroblasts and Improve Cell Migration by Interacting with the Extracellular Matrix

“…Dermal fibroblasts from diabetic subjects had diminished levels of pyruvate dehydrogenase kinase 4 (PDK4), an enzyme that regulates the glycolysis rate by phosphorylating the pyruvate dehydrogenase and the nuclear internalization of yes-associated protein 1 as well, which commands the expression of senescence markers. The authors demonstrated that restoring the levels of PDK4 with lentiviral infection in dermal fibroblasts not only avoided cellular senescence but also accelerated migration and wound closure [70]. Although we did not evaluate senescence markers in our HG fibroblasts, we observed several traits indicative of this condition, such as a decreased collagen production, a seven-fold decrease in proliferation along with three-fold lower protein content with respect to NG fibroblasts, and an increased oxidation of cytoplasmic proteins.…”