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（由申请人提供）：恶病质是慢性疾病如心力衰竭、肾衰竭和癌症的主要并发症。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）诱导骨骼肌萎缩，而胰岛素样生长因子1 （IGF-1）阻止它。Ang II破坏胰岛素和