American journal of physiology. Cell physiology最新文献

Cancer cachexia, or the unintentional loss of body weight in patients with cancer, is a multiorgan and multifactorial syndrome with a complex and largely unknown etiology; however, metabolic dysfunction and inflammation remain hallmarks of cancer-associated wasting. Although cachexia manifests with muscle and adipose tissue loss, perturbations to the gastrointestinal tract may serve as the frontline for both impaired nutrient absorption and immune-activating gut dysbiosis. Investigations into the gut microbiota have exploded within the past two decades, demonstrating multiple gut-tissue axes; however, the link between adipose and skeletal muscle wasting and the gut microbiota with cancer is only beginning to be understood. Furthermore, the most used anticancer drugs (e.g. chemotherapy and immune checkpoint inhibitors) negatively impact gut homeostasis, potentially exacerbating wasting and contributing to poor patient outcomes and survival. In this review, we 1) highlight our current understanding of the microbial changes that occur with cachexia, 2) discuss how microbial changes may contribute to adipose and skeletal muscle wasting, and 3) outline study design considerations needed when examining the role of the microbiota in cancer-induced cachexia.

Phenotypic changes to endometrial epithelial cells underpin receptivity to embryo implantation at the onset of pregnancy but the effect of hyperglycemia on these processes remains poorly understood. Here, we show that physiological levels of glucose (5 mM) abolished receptivity in the endometrial epithelial cell line, Ishikawa. However, embryo attachment was supported by 17 mM glucose as a result of glucose flux through the hexosamine biosynthetic pathway (HBP) and modulation of cell function via protein O-GlcNAcylation. Pharmacological inhibition of HBP or protein O-GlcNAcylation reduced embryo attachment in cocultures at 17 mM glucose. Mass spectrometry analysis of the O-GlcNAcylated proteome in Ishikawa cells revealed that myosin phosphatase target subunit 1 (MYPT1) is more highly O-GlcNAcylated in 17 mM glucose, correlating with loss of its target protein, phospho-myosin light chain 2, from apical cell junctions of polarized epithelium. Two-dimensional (2-D) and three-dimensional (3-D) morphologic analysis demonstrated that the higher glucose level attenuates epithelial polarity through O-GlcNAcylation. Inhibition of Rho (ras homologous)A-associated kinase (ROCK) or myosin II led to reduced polarity and enhanced receptivity in cells cultured in 5 mM glucose, consistent with data showing that MYPT1 acts downstream of ROCK signaling. These data implicate regulation of endometrial epithelial polarity through RhoA signaling upstream of actomyosin contractility in the acquisition of endometrial receptivity. Glucose levels impinge on this pathway through O-GlcNAcylation of MYPT1, which may impact endometrial receptivity to an implanting embryo in women with diabetes.NEW & NOTEWORTHY Understanding how glucose regulates endometrial function will support preconception guidance and/or the development of targeted interventions for individuals living with diabetes wishing to embark on pregnancy. We found that glucose can influence endometrial epithelial cell receptivity to embryo implantation by regulating posttranslational modification of proteins involved in the maintenance of cell polarity. Impaired or inappropriate endometrial receptivity could contribute to fertility and/or early pregnancy complications caused by poor glucose control.

Roberts et al. have provided an insightful counterpoint to our review article on the utility of the synergist ablation model. The purpose of this review is to provide some further dialogue regarding the strengths and weaknesses of the synergist ablation model. Specifically, we highlight that the robustness of the model overshadows surgical limitations. We also compare the transcriptomic responses to synergist ablation in mice and resistance exercise in humans to identify common pathways. We conclude that "cell growth is cell growth" and that the mechanisms available to cells to accumulate biomass and increase in size are similar across cell types and independent of the rate of growth.

Chronic hypoxia (CH) is commonly associated with various cardiovascular diseases, with cardiac hypertrophy being the most frequently observed alteration. Metabolic remodeling is another consequence seen in the hypoxic heart. However, the mechanistic linkage between metabolic remodeling and cardiac hypertrophy in the hypoxic heart remains unclear. In this study, wild-type C57BL/6J mice were subjected to CH for 4 wk. Echocardiography and morphological analysis were used to assess the cardiac effects. We found that 4 wk of CH led to significant cardiac hypertrophy in the mice, whereas cardiac function remained unchanged compared with normoxic mice. In addition, CH induced an elevation in cardiac alpha-ketoglutarate (α-KG) content. Promoting α-KG degradation in the CH hearts prevented CH-induced cardiac hypertrophy but led to noticeable cardiac dysfunction. Mechanistically, α-KG promoted the transcription of hypertrophy-related genes by regulating histone methylation. Silencing lysine-specific demethylase 5 (KDM5), a histone demethylation enzyme, blunted α-KG-induced transcription of hypertrophy-related genes. These data suggest that α-KG is required for CH-induced cardiac remodeling, thus establishing a connection between metabolic changes and cardiac remodeling in hypoxic hearts.NEW & NOTEWORTHY We reported that alpha-ketoglutarate (α-KG) is indispensable for chronic hypoxia (CH)-induced cardiac remodeling, which builds the bridge between metabolic intermediates and cardiac remodeling.

Gap junctions are channels that allow for direct transmission of electrical signals between cells. However, the ability of one cell to be impacted or controlled by other cells through gap junctions remains unclear. In this study, heterocellular coupling between ON α retinal ganglion cells (α-RGCs) and displaced amacrine cells (ACs) in the mouse retina was used as a model. The impact of the extent of coupling of interconnected ACs on the synchronized firing between coupled ON α-RGC-AC pair was investigated using the dopamine 1 receptor (D1R) antagonist-SCH23390 and agonist-SKF38393. It was observed that the synchronized firing between the ON α-RGC-ACs pairs was increased by the D1R antagonist SCH23390, whereas it was eradicated by the agonist SKF38393. Subsequently, the signaling drive was investigated by infecting coupled ON α-RGC-AC pairs with the channelrhodopsin-2(ChR2) mutation L132C engineered to enhance light sensitivities. The results demonstrated that the spikes of ON α-RGCs (without ChR2) could be triggered by ACs (with ChR2) through the gap junction, and vice versa. Furthermore, it was observed that ON α-RGCs stimulated with 3-10 Hz currents by whole cell patch could elicit synchronous spikes in the coupled ACs, and vice versa. This provided direct evidence that the firing of one cell could be influenced by another cell through gap junctions. However, this phenomenon was not observed between OFF α-RGC pairs. The study implied that the synchronized firing between ON α-RGC-AC pairs could potentially be affected by the coupling of interconnected ACs. Additionally, one cell type could selectively control the firing of another cell type, thereby forcefully transmitting information. The key role of gap junctions in synchronizing firing and driving cells between α-RGCs and coupled ACs in the mouse retina was highlighted.NEW & NOTEWORTHY This study investigates the role of gap junctions in transmitting electrical signals between cells and their potential for cell control. Using ON α retinal ganglion cells (α-RGCs) and amacrine cells (ACs) in the mouse retina, the researchers find that the extent of coupling between ACs affects synchronized firing. Bidirectional signaling occurs between ACs and ON α-RGCs through gap junctions.

Skeletal muscle exhibits remarkable plasticity to adapt to stimuli such as mechanical loading. The mechanisms that regulate skeletal muscle hypertrophy due to mechanical overload have been thoroughly studied. Remarkably, our understanding of many of the molecular and cellular mechanisms that regulate hypertrophic growth were first identified using the rodent synergist ablation (SA) model and subsequently corroborated in human resistance exercise training studies. To demonstrate the utility of the SA model, we briefly summarize the hypertrophic mechanisms identified using the model and the following translation of these mechanism to human skeletal muscle hypertrophy induced by resistance exercise training.

The exchange protein directly activated by cAMP (EPAC) has been implicated in cardiac proarrhythmic signaling pathways including spontaneous diastolic Ca²⁺ leak from sarcoplasmic reticulum and increased action potential duration (APD) in isolated ventricular cardiomyocytes. The action potential (AP) lengthening following acute EPAC activation is mainly due to a decrease of repolarizing steady-state K⁺ current (IK_SS) but the mechanisms involved remain unknown. This study aimed to assess the role of EPAC1 and EPAC2 in the decrease of IK_SS and to investigate the underlying signaling pathways. AP and K⁺ currents were recorded with the whole cell configuration of the patch-clamp technique in freshly isolated rat ventricular myocytes. EPAC1 and EPAC2 were pharmacologically activated with 8-(4-chlorophenylthio)-2'-O-methyl-cAMP acetoxymethyl ester (8-CPTAM, 10 µmol/L) and inhibited with R-Ce3F4 and ESI-05, respectively. Inhibition of EPAC1 and EPAC2 significantly decreased the effect of 8-CPTAM on APD and IK_SS showing that both EPAC isoforms are involved in these effects. Unexpectedly, calmodulin-dependent protein kinase II (CaMKII) inhibition by AIP or KN-93, and Ca²⁺ chelation by intracellular BAPTA, did not impact the response to 8-CPTAM. However, inhibition of PLC/PKC and nitric oxide synthase (NOS)/PKG pathways partially prevents the 8-CPTAM-dependent decrease of IK_SS. Finally, the cumulative inhibition of PKC and PKG blocked the 8-CPTAM effect, suggesting that these two actors work along parallel pathways to regulate IK_SS upon EPAC activation. On the basis of such findings, we propose that EPAC1 and EPAC2 are involved in APD lengthening by inhibiting a K⁺ current via both PLC/PKC and NOS/PKG pathways. This may have pathological implications since EPAC is upregulated in diseases such as cardiac hypertrophy.NEW & NOTEWORHTY Exchange protein directly activated by cAMP (EPAC) proteins modulate ventricular electrophysiology at the cellular level. Both EPAC1 and EPAC2 isoforms participate in this effect. Mechanistically, PLC/PKC and nitric oxide synthase (NO)/PKG pathways are involved in regulating K⁺ repolarizing current whereas the well-known downstream effector of EPAC, calmodulin-dependent protein kinase II (CaMKII), does not participate. This may have pathological implications since EPAC is upregulated in diseases such as cardiac hypertrophy. Thus, EPAC inhibition may be a new approach to prevent arrhythmias under pathological conditions.