Metabolic remodeling of cardiomyocytes identified in phosphoinositide-dependent kinase 1-deficient mice

Abstract

Metabolic remodeling plays an essential role in the pathophysiology of heart failure (HF). Many studies have shown that the disruption of phosphoinositide-dependent protein kinase-1 (PDK1) caused severe and lethal HF; however, the metabolic pattern of PDK1 deletion remains ambiguous. 1H nuclear magnetic resonance-based metabolomics was applied to explore the altered metabolic pattern in Pdk1-deficient mice. Principle component analysis showed significant separation as early as 4 weeks of age, and dysfunction of metabolism precedes a morphological change in Pdk1-deficient mice. A time trajectory plot indicated that disturbed metabolic patterns were related to the pathological process of the HF in Pdk1-deficient mice, rather than the age of mice. Metabolic profiles demonstrated significantly increased levels of acetate, glutamate, glutamine, and O-phosphocholine in Pdk1 deletion mice. Levels of lactate, alanine, glycine, taurine, choline, fumarate, IMP, AMP, and ATP were significantly decreased compared with controls. Furthermore, PDK1 knockdown decreased the oxygen consumption rate in H9C2 cells as determined using a Seahorse XF96 Analyzer. These findings imply that the disruption of metabolism and impaired mitochondrial activity might be involved in the pathogenesis of HF with PDK1 deletion.

Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B‐cell lymphomas

“…This study is also the first to show the universal antitumor effect of the blockade of PDPK1 on BCLs, regardless of disease subtypes, in addition to MCL 10 . However, therapeutic targeting of PDPK1 may cause various unnecessary effects because PDPK1 regulates more than 20 downstream functional kinases associated with pleiotropic biological processes, such as immunity, bone formation, glucose metabolism, renal sodium transport, pH regulation, and mitochondrial activity 25–33 …”

“…10 However, therapeutic targeting of PDPK1 may cause various unnecessary effects because PDPK1 regulates more than 20 downstream functional kinases associated with pleiotropic biological processes, such as immunity, bone formation, glucose metabolism, renal sodium transport, pH regulation, and mitochondrial activity. [25][26][27][28][29][30][31][32][33] The on-and/or off-target-related adverse events remain almost unavoidable in cancer treatment using the molecular-targeted kinase inhibitors [34][35][36] ; however, we attempted to select an effector molecule responsible for the oncogenic property of PDPK1 to preserve antilymphoma efficacy and to avoid unnecessary adverse events as much as possible. Thus, it was critically important to find that, among a series of downstream effector molecules of PDPK1, RSK2 plays a central role, and AKT and S6K play subsidiary functional roles in the proliferation of BCL-derived cells.…”

Deficiency of Pdk1 drives heart failure by impairing taurine homeostasis through Slc6a6

“…[36][37][38] Previously, we have reported the metabolic abnormalities in cardiomyocytes of Pdk1 deficiency mice. 16 To explore the mechanism of Pdk1-induced cell apoptosis and oxidative damage, we carried out metabolism NMR-based metabolomics analysis of Pdk1 deficiency mice and controls. The volcano analysis and loading plot displayed that taurine was the major contributor to the abnormal metabolic pattern.…”

“…Metabolic disturbances can promote cardiomyocyte death by increasing reactive oxygen species production and apoptosis, leading to structural and functional changes in the heart 36–38 . Previously, we have reported the metabolic abnormalities in cardiomyocytes of Pdk1 deficiency mice 16 . To explore the mechanism of Pdk1 ‐induced cell apoptosis and oxidative damage, we carried out metabolism NMR‐based metabolomics analysis of Pdk1 deficiency mice and controls.…”

“…Additionally, Pdk1 ‐deficiency caused lethal (HF) 13–15 . Our previous study reported the metabolic abnormalities in cardiomyocytes of Pdk1 deficiency mice 16 . Nevertheless, the mechanism underlying Pdk1 ‐induced HF is not clear.…”