Muscle-Specific Nutritional Adaptations to Catabolic States

对分解代谢状态的肌肉特异性营养适应

• 批准号: 7989319
• 负责人: S. Russ Price
• 金额: $ 10万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-10 至 2010-11-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989319
• 关键词: 1-Phosphatidylinositol 3-Kinase; Actins; Acute; Adrenergic Agonists; Adrenergic Receptor; Affect; Atrophic; Attenuated; Biochemical; Cachexia; Calcineurin; Cardiac; Caspase; Cells; Chronic Kidney Failure; Chronically Ill; Clenbuterol; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Dominant-Negative Mutation; Enzymes; Event; Genetic Transcription; Glucocorticoids; Growth Factor; Homeostasis; Hormones; Insulin; Insulin-Like Growth Factor I; Knockout Mice; Link; Maintenance; Measures; Mediating; Modeling; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscular Atrophy; Myocardium; Nutritional; Outcome; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Price; Protein Biosynthesis; Protein Isoforms; Proteins; Proteolysis; Proto-Oncogene Proteins c-akt; Quality of life; Rattus; Recovery; Regulation; Reporting; Research Personnel; Role; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Stimulus; System; Technology; Tissues; Ubiquitin; Uremia; actin 2; caspase-3; cell type; cytokine; diabetic rat; improved; insight; mortality; multicatalytic endopeptidase complex; muscle form; prevent; pro-apoptotic protein; programs; protein complex; protein degradation; research study; response; therapeutic target; therapy design; transcription factor; ubiquitin-protein ligase; wasting

DESCRIPTION (provided by applicant): The maintenance of muscle mass requires a complex symphony of cellular responses. During muscle atrophy, an imbalance of hormones and cytokines shifts regulatory signaling pathways (e.g., PI3K/Akt) towards protein degradation by increasing the activities of the ubiquitin-proteasome system and caspase-3. These proteolytic responses are unique to skeletal muscle, despite the fact that all tissues are exposed to the same systemic signals. This atrophy program, if unabated, could result in a deleterious loss of muscle proteins. Induction of two muscle -specific E3 ubiquitin ligases, atrogin-1 and MuRF1, has been proposed to be a key part of the atrophy response. The FOXO transcription factors appear to play a key role in the shift towards protein degradation by increasing the transcription of these E3s and possible other proteolytic enzymes (e.g., caspase-3). Aim 1 will examine how the FOXOs affect protein sythesis and degradation in muscle cells. Studies in Aim 2 will determine if higher atrogin-1 levels increase the degradation of calcineurin (CaN), a key phosphatase in muscle cells. We propose that the decrease in CaN may provide a mechanism to moderate the severity of wasting by removing an enzyme that can activate (i.e., dephosphorylate) the proapoptotic protein BAD; active BAD increases caspase-3 activity (Aim 4). The decrease in CaN could prevent caspase-3 activity from becoming excessive without affecting other proteolytic responses. Aim 3 will demonstrate that BAD is regulated by multiple signaling pathways and is a critical determinant of caspase-3 activity in muscle. We also propose that the muscle-sparing effects of b2- adrenergic agonists result, in part, from a PKA-dependent increase in BAD phosphorylation and a subsequent reduction in caspase-3 activity (Aim 5). In summary, we believe that FOXO and BAD are key signaling proteins through which diverse physiologic stimuli regulate protein attrition via the ubiquitin- proteasome system and caspase-3, respectively. Our studies will provide evidence that these two proteolytic systems can function independently and as an integrated pathway that allows for close regulation of muscle mass in response to physiologic conditions. New information regarding the mechanisms of muscle atrophy may identify therapeutic targets to reduce morbidity and mortality of chronically ill patients and improve their quality of life.

描述（由申请人提供）：肌肉质量的维持需要复杂的细胞反应交响曲。在肌肉萎缩期间，激素和细胞因子的失衡会通过增加泛素蛋白 - 蛋白酶体系统和caspase-3的活性而转移调节信号通路（例如PI3K/AKT）向蛋白质降解。尽管所有组织都暴露于相同的全身信号，但这些蛋白水解反应是骨骼肌独有的。这个萎缩程序，如果不减弱，可能会导致肌肉蛋白的有害损失。已经提议诱导两种肌肉特异性E3泛素连接酶Atrogin -1和Murf1，是萎缩反应的关键部分。 FOXO转录因子似乎通过增加这些E3和可能的其他蛋白水解酶的转录（例如CASPase-3）而在向蛋白质降解的转移中起关键作用。 AIM 1将检查FOXO如何影响肌肉细胞中蛋白质的结论和降解。 AIM 2中的研究将确定较高的Atrogin-1水平是否会增加肌肉细胞中的关键磷酸酶的钙调神经酶（CAN）的降解。我们建议减少可以通过去除可以激活（即脱磷酸化）促凋亡蛋白不良的酶来提供一种机制来调节浪费的严重程度；主动不良增加caspase-3活性（AIM 4）。减少可以防止caspase-3活性变得过大，而不会影响其他蛋白水解反应。 AIM 3将证明不良受到多个信号通路的调节，并且是肌肉中caspase-3活性的关键决定因素。我们还建议，B2-肾上腺素激动剂的肌肉比较作用部分是由于PKA依赖性不良磷酸化的增加和随后的Caspase-3活性的降低（AIM 5）。总而言之，我们认为FOXO和BAD是关键信号蛋白，通过这些蛋白质分别通过泛素蛋白酶体系统和caspase-3来调节蛋白质损耗。我们的研究将提供证据表明，这两个蛋白水解系统可以独立起作用，并且可以作为综合途径，允许响应生理条件的肌肉质量密切调节。有关肌肉萎缩机制的新信息可能会确定降低慢性病患者发病率和死亡率并改善其生活质量的治疗靶标。

项目成果

Determinants of protein turnover in health and disease.

健康和疾病中蛋白质周转的决定因素。

• DOI: 10.1159/000057344
• 发表时间: 1998
• 期刊: Mineral and electrolyte metabolism.
• 作者: Newby,FD;Price,SR
• 通讯作者: Price,SR

Muscle atrophy in chronic kidney disease results from abnormalities in insulin signaling.

• DOI: 10.1053/j.jrn.2010.05.007
• 发表时间: 2010-09
• 期刊: Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation
• 作者: Price SR;Gooch JL;Donaldson SK;Roberts-Wilson TK
• 通讯作者: Roberts-Wilson TK

Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells.

• DOI: 10.1152/ajpcell.00617.2006
• 发表时间: 2007-05
• 期刊: American journal of physiology. Cell physiology
• 作者: Xiaonan H. Wang;Junping Hu;S. Price

Regulation of branched-chain ketoacid dehydrogenase flux by extracellular pH and glucocorticoids.

细胞外 pH 值和糖皮质激素对支链酮酸脱氢酶通量的调节。

• DOI: 10.1152/ajpcell.1997.272.6.c2031
• 发表时间: 1997
• 期刊: The American journal of physiology.
• 作者: Wang,X;Jurkovitz,C;Price,SR
• 通讯作者: Price,SR

Branched-chain amino acid catabolism in uremia: dual regulation of branched-chain alpha-ketoacid dehydrogenase by extracellular pH and glucocorticoids.

尿毒症中的支链氨基酸分解代谢：细胞外 pH 值和糖皮质激素对支链 α-酮酸脱氢酶的双重调节。

• 发表时间: 1997
• 期刊: Mineral and electrolyte metabolism.
• 作者: Wang,X;Jurkovitz,C;Price,SR
• 通讯作者: Price,SR