Dysfunctional PGC-1alpha expression in skeletal muscle during diabetes

糖尿病期间骨骼肌中 PGC-1α 表达功能失调

• 批准号: 8660225
• 负责人: S. Russ Price
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660225
• 关键词: Affect; Animals; Atrophic; Attenuated; Biochemical; CREB1 gene; Calcineurin; Calcineurin inhibitor; Calcium; Chronic; Chronic Disease; Chronic Kidney Failure; Comorbidity; Cyclic AMP-Responsive DNA-Binding Protein; Cyclosporine; Data; Denervation; Dexamethasone; Diabetes Mellitus; Disease; Down-Regulation; Energy Metabolism; Exercise; F Box Domain; FK506; Fasting; Fatigue; Future; Gene Expression; Genetic Transcription; Glucocorticoids; Goals; Growth; Innovative Therapy; Insulin Resistance; Intervention; Link; Maintenance; Mediating; Messenger RNA; Modeling; Mus; Muscle; Muscle Cells; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; PPAR gamma; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Phosphorylation; Prednisone; Protein Serine/Threonine Phosphatase; Proteins; Quality of life; Rattus; Rehabilitation therapy; Reporting; Research; Risk Factors; Rodent; Signal Pathway; Signal Transduction; Skeletal Muscle; System; Testing; Therapeutic immunosuppression; Training; Transcription Coactivator; Transducers; Transgenic Mice; Transgenic Organisms; Transplant Recipients; Veterans; base; design; gene induction; genetic regulatory protein; improved; innovation; mortality; muscle form; myocyte-specific enhancer-binding factor 2; nuclear factors of activated T-cells; overexpression; programs; promoter; protein degradation; protein function; protein metabolism; public health relevance; receptor; response; transcription factor; wasting

DESCRIPTION (provided by applicant): Skeletal muscle atrophy is a frequent co-morbidity of diabetes mellitus (DM) and other chronic diseases that causes fatigue and weakness. Loss of muscle mass also is a risk factor for mortality in these conditions. Despite significant advances in understanding the mechanisms causing muscle loss,attempts to develop pharmaceutical interventions to attenuate atrophy have been unsuccessful. In contrast, exercise can have beneficial effects on muscle in chronic conditions although how its effects are achieved remains unclear. We and others have reported that the level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha, a transcriptional coactivator protein, is decreased in skeletal muscle during DM and in cultured myotubes treated with glucocorticoids to induced insulin resistance and atrophy. This is notable because PGC-alpha expression in normal skeletal muscle is increased by exercise and transgenic overexpression of PGC-1alpha protects against muscle loss. PGC-1alpha is a critical "master regulator" that integrates energy and protein metabolism. It functions by inhibiting the activity of the F Box O (FOXO) transcription factors which mediate the atrophy program. Understanding how exercise maintains muscle function in DM will improve our ability to treat fatigue and weakness. To accomplish this goal, we must first understand the biochemical basis for dysregulation of PGC1alpha expression during atrophy. This project will test the hypothesis that the reduction in PGC-1alpha expression during DM-related atrophy results from abnormal signaling through one or more pathways that are regulated by calcineurin (Cn), a calcium-activated serine/threonine phosphatase. We will examine the myocyte enhancer factor 2 (MEF2) and cytoplasmic nuclear factor of activated T cells (NFATc) pathways because both transcription factors are Cn substrates that have been reported to regulate PGC-1alpha transcription in normal skeletal muscle. The third pathway to be studied is the Transducer of Regulated CREB 1 (TORC1)/cyclic AMP-responsive element (CRE)-binding protein (CREB) pathway. TORC1 is a transcription coactivator of CREB that is activated by Cn and required for PGC-1alpha expression. Our preliminary data suggests that TORC1 function is impaired during atrophy. Once the mechanisms of PGC-1alpha dysregulation are characterized, we will test whether exercise improves Cn signaling in DM mice, thus leading to an increase in muscle PGC-1alpha expression. When the aims of this project are complete, we will have identified the Cn-related pathways that are responsible for the reduction in PGC-1alpha expression, and thus contribute to atrophy. In addition, we will have determined which of these pathways in DM muscle respond to exercise. This information could be useful for designing innovative and protein-targeted treatments and rehabilitation therapies of Veterans with DM. Results of the proposed studies also may be relevant to Veteran transplant recipients whose immunosuppressive therapies include glucocorticoids and/or calcineurin inhibitors (i.e., cyclosporine A, FK506). Many transplant recipients have reduced lean body mass due the catabolic effects of chronic diseases while others are challenged to maintain their muscle mass due to maintenance prednisone therapy. Use of Cn inhibitors could have a negative impact on both types of patients. Lastly, our results could be broadly applicable to Veterans suffering from many types of debilitating diseases associated with atrophy.

描述（由申请人提供）： 骨骼肌萎缩是糖尿病（DM）和其他导致疲劳和无力的慢性疾病的常见合并症。在这些条件下，肌肉质量的损失也是死亡率的危险因素。尽管在理解导致肌肉损失的机制方面取得了重大进展，但尝试开发药物干预以减轻萎缩的尝试并未成功。相比之下，运动在慢性条件下对肌肉产生有益的影响，尽管如何实现其影响尚不清楚。我们和其他人报告说，过氧化物酶体增殖物激活的受体γ共激活剂1-alpha（PGC-1alpha（一种转录共激活蛋白PGC-1alpha）在DM期间骨骼肌和培养的肌管中用糖皮质激素对胰岛素的耐药性和胰岛素的抑制作用而降低骨骼肌的骨骼肌肉，因为胰岛素的球和胰岛素的表现为PGC。通过锻炼和pgc-1alpha的过度表达，可以防止肌肉损失。PGC-1Alpha是一个至关重要的“主调节器”，可以通过抑制F Box O（Foxo）的活性来培养效果，从而抑制F Box O（Foxo）的活性，从而抑制F box o（foxo）的活性。 PGC1Alpha表达在萎缩期间的生化基础。我们将检查活化T细胞（NFATC）途径的心肌细胞增强因子2（MEF2）和细胞质核因子，因为两种转录因子都是CN底物，据报道，在正常骨骼肌中调节PGC-1Alpha转录。要研究的第三个途径是调节的CREB ​​1（TORC1）/环状AMP反应元件（CRE）结合蛋白（CREB）途径的传感器。 TORC1是CREB的转录共激活因子，被CN激活，并且需要PGC-1Alpha表达。我们的初步数据表明，在萎缩期间，TORC1功能受损。一旦表征了PGC-1Alpha失调的机制，我们将测试运动是否改善DM小鼠的CN信号传导，从而导致肌肉PGC-1Alpha表达的增加。当该项目的目标完成后，我们将确定导致PGC-1Alpha表达降低的CN相关途径，从而导致萎缩。此外，我们将确定DM肌肉中的哪些途径对运动有反应。这些信息对于设计具有DM的退伍军人的创新和蛋白质靶向疗法和康复疗法可能很有用。拟议的研究的结果也可能与退伍军人的移植受者有关，其免疫抑制疗法包括糖皮质激素和/或钙调蛋白抑制剂（即环孢素A，FK506）。由于慢性疾病的分解代谢作用，许多移植接受者的体重降低了，而其他人由于维持泼尼松治疗而受到挑战以维持其肌肉质量。使用CN抑制剂可能会对两种类型的患者产生负面影响。最后，我们的结果可能广泛适用于患有与萎缩相关的许多类型衰弱疾病的退伍军人。