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TWEAK/Fn14/UPR Signaling in Skeletal Muscle Wasting

骨骼肌萎缩中的 TWEAK/Fn14/UPR 信号转导

基本信息

批准号：
10660397
负责人：
ASHOK KUMAR
金额：
$ 55.16万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660397
关键词：
ATF6 gene Ablation Acceleration Adult Advanced Malignant Neoplasm Aging Antibodies ApcMin/+ mice Apoptosis Promoter Atrophic Attenuated Binding Cachexia Cancer Model Cancer Patient Cell Surface Receptors Chronic Chronic Disease Complication Denervation Development Disease Elderly Endoplasmic Reticulum Eukaryotic Initiation Factors Exercise Gene Expression Genetic Homeostasis In Vitro Individual Induction of Apoptosis Inflammation Inflammatory Inositol KRASG12D Knockout Mice Link Malignant Neoplasms Mediating Mediator Membrane Metabolic Metabolic dysfunction Mitochondria Modeling Molecular Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Neuromuscular Junction Nutrient Organelles Oxidative Stress PRKR gene Pathway interactions Patients Phosphotransferases Population Prevention Prevention approach Prokaryotic Initiation Factor-2 Protein Biosynthesis Protein Secretion Proteins RNA Splicing Regulation Reporting Repression Role Signal Pathway Signal Transduction Skeletal Muscle Skeletal Muscle Neoplasm Stress Syndrome System TNF gene Therapeutic XBP1 gene activating transcription factor 1 aged arm cancer cachexia cell injury cytokine endoplasmic reticulum stress experimental study frailty improved in vivo knock-down member mouse model muscle form new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression pancreatic cancer model pre-clinical prevent protein degradation protein folding receptor response sarcopenia sensor skeletal muscle differentiation skeletal muscle growth skeletal muscle wasting tissue degeneration tumor

项目摘要

ABSTRACT Skeletal muscle wasting/cachexia is a devastating complication of a number of chronic disease states, such as cancer and in the elderly population. Muscle wasting involves an imbalance in the rates of protein synthesis and degradation, functional denervation, metabolic abnormalities, and loss of mitochondrial content and function. TWEAK is a proinflammatory cytokine that binds to cell surface receptor Fn14 to activate multiple intracellular signaling pathways. We have found that the expression of Fn14 is increased in skeletal muscle of mouse models of cancer cachexia and in aged mice. Skeletal muscle-specific ablation of Fn14 inhibits muscle wasting in a murine model of cancer cachexia. TWEAK represses the rate of protein synthesis in skeletal muscle both in vivo and in vitro. Furthermore, the TWEAK-Fn14 system regulates ER stress- induced unfolded protein response (UPR) in skeletal muscle of tumor-bearing mice. In addition, our experiments demonstrate that targeted inhibition of the PERK and/or IRE1/XBP1 arms of the UPR improves protein synthesis in skeletal muscle of mice. However, the role of the TWEAK-Fn14 system and UPR pathways in the regulation of skeletal muscle mass and function during cancer cachexia and aging remains completely unknown. In this project, we will investigate the role of TWEAK/Fn14/UPR signaling axis in skeletal muscle atrophy and whether targeted genetic ablation of Fn14 or components of the UPR attenuate muscle wasting in preclinical mouse models of cancer cachexia and during aging. Based on our preliminary results, we hypothesize that the TWEAK/Fn14 system causes skeletal muscle wasting through the activation of the PERK and the IRE1α/XBP1 arms of the UPR during aging and cancer cachexia. Our specific aims are to: (I) Investigate the role of the TWEAK/Fn14 system in skeletal muscle wasting during aging and cancer cachexia, and (II) Investigate the mechanisms by which TWEAK/Fn14-induced activation of the UPR pathways cause skeletal muscle wasting during aging and cancer cachexia. Our proposed studies will identify key mechanisms responsible for the loss of skeletal muscle mass. Successful completion of this project will provide strong basis for the development of new therapies for sarcopenia and cancer cachexia.

摘要