Angiotensin II, IGF-1 and Skeletal Muscle Atrophy

血管紧张素 II、IGF-1 和骨骼肌萎缩

• 批准号: 8386880
• 负责人: PATRICE DELAFONTAINE
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386880
• 关键词: Adenosine Monophosphate; Adult; Affect; Angiotensin II; Angiotensin II Receptor; Atrophic; Biology; Blood Pressure; Body Weight decreased; Cachexia; Cardiovascular Diseases; Catabolism; Cell fusion; Cells; Chronic; Chronic Disease; Chronic Kidney Failure; Chronic Obstructive Airway Disease; Clinical; Complication; Congestive Heart Failure; Cytochromes; Data; Desire for food; Development; Diabetes Mellitus; Direct Lytic Factors; Disease; End stage renal failure; Enzyme Activation; Equilibrium; Functional disorder; Genetic Transcription; Goals; Grant; Heart failure; Human; IGFBP5 gene; Impairment; Infusion procedures; Injury; Innovative Therapy; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Interleukin-6; Kidney; Kidney Diseases; Kidney Failure; Malignant Neoplasms; Mediating; Metabolism; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Muscle Proteins; Muscle satellite cell; Muscular Atrophy; Natural regeneration; Organ; Outcomes Research; Oxidases; Pathogenesis; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Protein Kinase; Public Health; Renal carcinoma; Renin-Angiotensin System; Resistance; Ribonucleosides; Role; Signal Transduction; Skeletal Muscle; Sodium Chloride; Staging; System; Therapeutic Intervention; Tissue Sample; Tissues; Transgenic Organisms; Type 2 Angiotensin II Receptor; Ubiquitin; Up-Regulation; Water; cerebrovascular; energy balance; glucose metabolism; human tissue; in vivo; insight; insulin signaling; mitochondrial dysfunction; mortality; multicatalytic endopeptidase complex; muscle form; muscle metabolism; muscle regeneration; notch protein; novel; overexpression; prevent; protective effect; protein degradation; protein metabolism; protein phosphatase 2C; receptor; regenerative; repaired; response; self-renewal; skeletal muscle wasting; ubiquitin ligase; ubiquitin-protein ligase; wasting

DESCRIPTION (provided by applicant): Cachexia is a major complication of chronic diseases such as heart failure, kidney failure and cancer. In these conditions the renin-angiotensin system (RAS) is often activated. We have shown that Angiotensin II (Ang II) induces skeletal muscle wasting, while Insulin-like growth factor 1 (IGF-1) prevents it. Ang II disrupts insulin and IGF-1 signaling, induces mitochondrial dysfunction, depletes muscle ATP, and inhibits 5'-Adenosine Monophosphate Activated Protein Kinase (AMPK) signaling, preventing the normal response to energy depletion. Activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restores energy balance and prevents Ang II wasting, indicating that AMPK plays a critical role in Ang II effects on skeletal muscle. Ang II also reduces the regenerative capacity of skeletal muscle following injury by depleting the muscle stem cell (MuSC) compartment, likely via AT1a receptor (AT1aR) mediated inhibition of Notch signaling. Muscle specific overexpression of IGF-1 activates AMPK, increases MuSC, and prevents Ang II-induced wasting, implicating AMPK and MuSC as key points of convergence for the opposing effects of Ang II and IGF- 1 in muscle. The long-term objectives of this project are to understand how Ang II alters skeletal muscle biology and how IGF-1 exerts its protective effects against Ang II-induced wasting; we will achieve these goals through three specific aims: Specific Aim 1. To demonstrate that impairment of energy balance and AMPK signaling mediate ANG II-induced skeletal muscle atrophy and to determine the mechanisms involved. We will use Ang II infusion with skeletal muscle specific AT1aR-/- mice, AMPK kinase dead (AMPK- KD) mice, Akt-/- mice, and constructs overexpressing constitutively active AMPK or Akt to examine whether the negative effects of Ang II on energy balance are mediated by alterations in AMPK and/or Akt signaling, and to ascertain the mechanisms of AICAR mediated rescue. We will also study human skeletal muscle tissue samples. Specific Aim 2: To demonstrate that Ang II induced insulin/IGF-1 resistance and dysregulation of glucose and protein metabolism are prevented by IGF-1 activation of AMPK. We will utilize AMPK-KD mice, MLC-IGF-1 mice (muscle specific IGF-1 transgenics), muscle specific IGF-1R-/- mice to assess effects of Ang II on insulin/IGF-1 signaling, to examine if rescue effects of IGF-1 are AMPK-dependent and study the effects of AICAR. Specific Aim 3: To demonstrate that Ang II and IGF-1 regulate muscle stem cells and, via this mechanism, alter muscle regeneration. We will use human tissue samples, MLC-IGF-1 mice, AT1aR-/- mice, Myf5LacZ/+ mice and the cardiotoxin-injury model to examine mechanisms whereby Ang II inhibits and IGF-1 stimulates muscle regeneration. Our results will provide key insights into mechanisms whereby Ang II impairs skeletal muscle metabolism, depletes MuSC and inhibits regeneration; as well as insights into novel effects of IGF-1 on skeletal muscle. These findings will allow development of innovative therapies to treat cachexia in chronic conditions in which the RAS is activated. PUBLIC HEALTH RELEVANCE: Skeletal muscle wasting (cachexia) is a major public health issue contributing to the morbidity and mortality of a variety of disease states, including congestive heart failure, chronic renal failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer. This proposal will focus on elucidating the mechanisms of wasting caused by angiotensin II and the mechanisms of rescue by insulin-like growth factor 1, and should provide new avenues for targeted and specific therapeutic interventions.

描述（申请人提供）：恶病质是心力衰竭、肾衰竭和癌症等慢性疾病的主要并发症。在这些情况下，肾素-血管紧张素系统（RAS）经常被激活。我们已经证明，血管紧张素 II (Ang II) 会导致骨骼肌萎缩，而胰岛素样生长因子 1 (IGF-1) 则可以预防骨骼肌萎缩。 Ang II 会破坏胰岛素并 IGF-1 信号传导可诱导线粒体功能障碍，消耗肌肉 ATP，并抑制 5'-单磷酸腺苷激活蛋白激酶 (AMPK) 信号传导，从而阻止对能量消耗的正常反应。用 5-氨基咪唑-4-甲酰胺核糖核苷 (AICAR) 激活 AMPK 可恢复能量平衡并防止 Ang II 消耗，表明 AMPK 在 Ang II 对骨骼肌的影响中发挥着关键作用。 Ang II 还可能通过 AT1a 受体 (AT1aR) 介导的 Notch 信号传导抑制，消耗肌肉干细胞 (MuSC) 区室，从而降低受伤后骨骼肌的再生能力。 IGF-1 的肌肉特异性过度表达可激活 AMPK，增加 MuSC，并防止 Ang II 诱导的消耗，这表明 AMPK 和 MuSC 是 Ang II 和 IGF-1 在肌肉中产生相反作用的关键点。该项目的长期目标是了解 Ang II 如何改变骨骼肌生物学以及 IGF-1 如何发挥其针对 Ang II 引起的消耗的保护作用；我们将通过三个具体目标来实现这些目标： 具体目标 1. 证明能量平衡和 AMPK 信号传导受损介导 ANG II 诱导的骨骼肌萎缩，并确定所涉及的机制。我们将使用 Ang II 输注骨骼肌特异性 AT1aR-/- 小鼠、AMPK 激酶死亡 (AMPK-KD) 小鼠、Akt-/- 小鼠，并构建过表达组成型活性 AMPK 或 Akt，以检查 Ang II 是否对能量平衡由 AMPK 和/或 Akt 信号传导的改变介导，并确定 AICAR 介导的救援机制。我们还将研究人类骨骼肌组织样本。具体目标 2：证明 Ang II 诱导的胰岛素/IGF-1 抵抗以及葡萄糖和蛋白质代谢失调可通过 IGF-1 激活 AMPK 来预防。我们将利用 AMPK-KD 小鼠、MLC-IGF-1 小鼠（肌肉特异性 IGF-1 转基因小鼠）、肌肉特异性 IGF-1R-/- 小鼠来评估 Ang II 对胰岛素/IGF-1 信号传导的影响，以检查是否可以挽救IGF-1 的作用依赖于 AMPK，并研究 AICAR 的作用。具体目标 3：证明 Ang II 和 IGF-1 调节肌肉干细胞，并通过这种机制改变肌肉再生。我们将使用人体组织样本、MLC-IGF-1 小鼠、AT1aR-/- 小鼠、Myf5LacZ/+ 小鼠和心脏毒素损伤模型来研究 Ang II 抑制和 IGF-1 刺激肌肉再生的机制。我们的研究结果将为 Ang II 损害骨骼肌代谢、消耗 MuSC 和抑制再生的机制提供重要见解；以及对 IGF-1 对骨骼肌的新影响的见解。这些发现将有助于开发创新疗法来治疗 RAS 被激活的慢性病中的恶病质。 公共卫生相关性：骨骼肌消耗（恶病质）是一个主要的公共卫生问题，导致多种疾病状态的发病率和死亡率，包括充血性心力衰竭、慢性肾衰竭、慢性阻塞性肺病、糖尿病和癌症。该提案将重点阐明血管紧张素 II 引起的消瘦机制和胰岛素样生长因子 1 的救援机制，并为有针对性和具体的治疗干预措施提供新途径。