Recovery from Cachexia in Heart and Skeletal Muscle

描述（由申请人提供）：背景。充血性心力衰竭（CHF）是一种全身性疾病。它植根于神经激素激活，其特征是氧化应激和软组织的浪费，最终导致恶病质，通常被认为是不可逆的。然而，长时间卧床休息导致CHF持续恢复和心脏大小正常化;左心室辅助装置也是如此。从恶病质中恢复所涉及的机制是令人感兴趣的。神经激素戒断的作用可以推断，但没有定义。对接受4周醛固酮/盐治疗（ALDOST）的恶病质大鼠的初步研究发现，心脏和骨骼肌的转录组发生了改变，包括泛素特异性蛋白酶2上调和胰岛素生长因子（IGF）-1下调。体重和萎缩的肌肉在停用ALDOST后4周内自然恢复，在继续ALDOST并补充ALDO受体拮抗剂螺内酯（Spiro）4周后辅助恢复。慢性ALDOST第4周观察到的消瘦可通过停药、与干扰醛固酮受体结合、Ca 2+超载或氧化应激的药物联合治疗、或单独使用合成代谢药物或与选择性ALDO受体拮抗剂依普利酮（Epler）联合使用来逆转。从基因表达异常中恢复应该让我们深入了解每种药物的有效性和缺点。计划我们将使用ALDOST模型（其中甲状旁腺素介导的细胞内Ca 2+超载诱导氧化应激已被证明在临床前阶段（第1周），随后恶病质（第4周）），以解决导致恶病质的分子事件的进展。由ALDOST引起的神经激素异常可随时停用。基因表达阵列使我们能够揭示导致恶病质的途径，以及心脏和骨骼肌基因组、生物化学和结构的异常在何种程度上被每次治疗逆转。目标一：表征慢性ALDOST临床前（第1周）和病理（第4周）阶段心肌和骨骼肌中的生化和基因表达异常，以及4周后停用ALDOST自然恢复的潜力;并将这种逆转与6周和8周ALDOST包括第4周开始的2周或4周Spiro或Epler联合治疗时的辅助恢复进行比较。目标二：为了表征在第6和8周ALDOST时患病心脏和骨骼肌中响应于由减弱的细胞内Ca 2+过载提供的辅助恢复的恢复和分子事件，使用a）西那卡塞，一种重置甲状旁腺Ca 2+敏感受体以抑制继发性甲状旁腺功能亢进（SHPT）的拟钙剂，B）甲状旁腺素，一种L型Ca 2+通道阻断剂，其在SHPT的情况下防止Ca 2+进入，和c）通过用N-乙酰半胱氨酸（抗氧化剂）消除氧化应激，每种都在第4周开始。目标3：为了确定当在第4周ALDOST引入4周合成代谢剂治疗时，单独或与Epler一起输注IGF-1，是否在患病心肌和骨骼肌的转录组和结构中出现恢复的分子证据。充血性心力衰竭（CHF）是一个主要的健康问题。晚期CHF伴有神经激素激活和组织消耗或恶病质，预后不良，被认为是不可逆的。本研究将探讨醛固酮/盐治疗大鼠恶病质恢复的分子机制，以及通过停药或药物干预可以实现恶病质恢复的情况。公共卫生相关性：充血性心力衰竭（CHF）是一个主要的健康问题。晚期CHF伴 神经激素激活和组织浪费或恶病质具有不祥的预后，并且被认为是不可逆的。本研究将探讨醛固酮/盐治疗大鼠恶病质恢复的分子机制，以及通过停药或药物干预可以实现恶病质恢复的情况。

DESCRIPTION (provided by applicant): Background. Congestive heart failure (CHF) is a systemic illness. Rooted in neurohormonal activation, it features oxidative stress and a wasting of soft tissues eventuating in cachexia, generally considered irreversible. However, prolonged bed rest leads to a sustained recovery from CHF and normalization in heart size; so too does a left ventricular assist device. Mechanisms involved in the recovery from cachexia are of interest. The role of neurohormonal withdrawal could be inferred but is not defined. Preliminary studies in cachectic rats receiving 4 wks aldosterone/salt treatment (ALDOST) identified altered transcriptome of heart and skeletal muscle that included upregulated ubiquitin-specific protease2 and downregulated insulin growth factor (IGF)-1. A natural recovery in body weight and atrophic muscle occurred over 4 wks with the discontinuation of ALDOST, and an assisted recovery when ALDOST was continued and supplemented with an ALDO receptor antagonist, spironolactone (Spiro), for 4 wks. Hypothesis. The wasting seen at wk 4 of chronic ALDOST can be reversed by its discontinuation, by cotreatment with agents interfering with either aldosterone receptor binding, Ca2+ overloading, or oxidative stress, or by an anabolic agent alone or in combination with eplerenone (Epler), a selective ALDO receptor antagonist. Recovery from gene expression abnormalities should give us insights into the effectiveness and shortcomings of each agent. Plan. We will use the ALDOST model (in which parathyroid hormone-mediated intracellular Ca2+ overloading with induction of oxidative stress has been demonstrated during a preclinical stage (wk 1) followed by cachexia (wk 4)) to address the progression of molecular events leading to cachexia. Neurohormonal abnormality, caused by ALDOST, can be readily discontinued. Gene expression arrays allow us to reveal pathways leading to cachexia and to what extent abnormalities in heart and skeletal muscle genome, biochemistry and structure are reversed by each treatment. Aim #1: to characterize biochemical and gene expression abnormalities at preclinical (wk 1) and pathologic (wk 4) stages of chronic ALDOST in cardiac and skeletal muscle, together with their potential for natural recovery by discontinuing ALDOST after 4 wks; and to compare this reversal to assisted recovery when 6 and 8 wks ALDOST includes 2 or 4 wks of Spiro or Epler cotreatment begun at wk 4. Aim#2: to characterize recovery and molecular events in diseased heart and skeletal muscle at wks 6 and 8 ALDOST in response to assisted recovery provided by attenuated intracellular Ca2+ overloading using a) cinacalcet, a calcimimetic that resets the parathyroid glands' Ca2+- sensing receptor to suppress secondary hyperparathyroidism (SHPT), b) amlodipine, an L-type Ca2+ channel blocker that prevents Ca2+ entry in the setting of SHPT, and c) by negating oxidative stress with N-acetylcysteine, an antioxidant, each begun at wk 4. Aim #3: to determine whether molecular evidence of recovery would appear in the transcriptome and structure of diseased cardiac and skeletal muscle, when 4 wks treatment with an anabolic agent is introduced at wk 4 ALDOST, using an infusion of IGF-1, given alone or with Epler. Congestive heart failure (CHF) is a major health problem. Advanced CHF accompanied by neurohormonal activation and a wasting of tissues, or cachexia, carries an ominous prognosis and is thought to be irreversible. This study will address molecular mechanisms involved in the recovery from cachexia that appears in rats treated with aldosterone/salt and where recovery from this regimen can be achieved by its withdrawal or pharmacologic intervention. PUBLIC HEALTH RELEVANCE: Congestive heart failure (CHF) is a major health problem. Advanced CHF accompanied by neurohormonal activation and a wasting of tissues, or cachexia, carries an ominous prognosis and is thought to be irreversible. This study will address molecular mechanisms involved in the recovery from cachexia that appears in rats treated with aldosterone/salt and where recovery from this regimen can be achieved by its withdrawal or pharmacologic intervention.