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Sarcopenia in cirrhosis is mediated by a hyperammonemic stress response

肝硬化中的肌肉减少症是由高氨血症应激反应介导的

基本信息

批准号：
9976523
负责人：
Srinivasan Dasarathy
金额：
$ 57.95万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976523
关键词：
ATF6 gene Abbreviations Acids Amino Acid Transporter Amino Acids Amino Acyl-tRNA Synthetases Ammonia Autophagocytosis Binding Proteins Biochemical Branched-Chain Amino Acids CCL21 gene Caliber Catabolism Cell model Cellular Stress Cellular Stress Response Characteristics Cirrhosis Clinical Complex Complication DNA Damage Data Diamines Edetic Acid Embryo Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Enzymes Equilibrium Ethylenes Eukaryotic Initiation Factor-2 Event Experimental Models Exposure to FRAP1 gene Feedback Fibroblasts Foundations Genetic Transcription Glutamate-Ammonia Ligase Glutamine Green Fluorescent Proteins Growth Homologous Gene Human Hyperammonemia Impairment Inositol Intervention Leucine Limb structure Link Liver diseases MAPK8 gene Magnetic Resonance Imaging Mass Fragmentography Mediating Mediator of activation protein Molecular Mus Muscle Muscle Fibers Muscular Atrophy Outcome Pathway interactions Patients Phase Phenylalanine Phosphorylation Phosphotransferases Physiological Plasma Polymerase Chain Reaction Prevalence Protein Biosynthesis Protein Kinase Protein Synthesis Inhibition Protein phosphatase Proteins Proteolysis Publishing RNA RNA Splicing Recovery Rodent Model Signal Pathway Signal Transduction Skeletal Muscle Supplementation Surgical Portacaval Shunt Surgical Portosystemic Shunt Testing Thapsigargin Therapeutic Therapeutic Intervention Time Tissues Transfer RNA Translation Initiation Tunicamycin Variant activating transcription factor activating transcription factor 4 adaptive intervention ammonium acetate biological adaptation to stress clinical translation effective therapy endoplasmic reticulum stress experimental study extracellular gain of function hepatic ureagenesis in vivo inhibitor/antagonist mRNA Transcript Degradation mouse model muscle form new therapeutic target novel prevent proteostasis purine metabolism response sarcopenia sensor skeletal muscle wasting small molecule inhibitor solute stressor targeted treatment therapeutic target transcription factor CHOP uptake

项目摘要

ABSTRACT In cirrhosis, hyperammonemia is a consistent abnormality due to impaired hepatic ureagenesis and portosystemic shunting. Sarcopenia or loss of skeletal muscle mass is a major complication of hyperammonemia in cirrhosis and portosystemic shunting. Despite nearly universal recognition of the prevalence and adverse clinical consequences of sarcopenia, there are no effective therapies because the mechanisms of muscle loss in cirrhosis are not well understood. Loss of muscle mass occurs due to dysregulated protein homeostasis or proteostasis with impaired protein synthesis and increased proteolysis by autophagy. Protein homeostasis during cellular stress is achieved by activating an integrated stress response (ISR) in response to eIF2α phosphorylation via the activating transcription factor 4. Ammonia is a cellular stressor that is generated during amino acid catabolism, purine metabolism and synthesis in the gut. We identified a unique cellular stress response in the skeletal muscle that we have termed the hyperammonemic stress response (HASR). During HASR, we observed an increased phosphorylation and activation of the eIF2α kinase and amino acid deficiency sensor, general control nonderepressed 2 (GCN2) that is reversed by L- leucine supplementation. These perturbations resemble an amino acid deficiency response despite increased cellular L-leucine concentrations during hyperammonemia. Interestingly, we also observed that only one of the 3 components of the unfolded protein response (UPR), IRE1α, is activated during HASR. Interestingly, the other 2 limbs of the UPR: PERK, the classical mediator of Endoplasmic Reticulum (ER) stress and ATF6 were not activated during HASR. Unlike the cellular stress responses with eIF2α phosphorylation, the integrated stress response with induction of ATF4 and its targets that support translational recovery were also not observed during HASR. These observations show that HASR shares some characteristics of amino acid deficiency response (without deficiency) and some features of the UPR. Our preliminary and published data suggest a concentration and time dependent initial adaptive that progresses to a maladaptive phase in the skeletal muscle results in sarcopenia. We hypothesized that HASR is activated in response to hyperammonemia and involves a GCN2/mTORC1 axis that represses protein synthesis and induces an adaptive response of increased amino acid uptake and proteostasis control via the amino acid transporter SLC7A5. We also hypothesize that during HASR, only the IRE1α/XBP1s is activated with increased autophagy and mRNA degradation via RIDD (Regulated IRE1α dependent decay). The mechanisms of HASR and interventions that can increase protective adaptations to hyperammonemia in myotubes will be studied in a comprehensive array of cellular and rodent models of hyperammonemia and in the skeletal muscle of human cirrhotics in 3 specific aims. In each aim, a specific molecular therapeutic intervention will be tested with the potential for rapid clinical translation to reverse and potentially prevent sarcopenia in liver disease.

摘要