Recovery from Cachexia in Heart and Skeletal Muscle

描述（由申请人提供）：背景。充血性心力衰竭是一种全身性疾病。它植根于神经激素的激活，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，长时间卧床休息可导致心力衰竭的持续恢复和心脏大小的正常化；左心室辅助装置也是如此。恶病质恢复的机制引起了人们的兴趣。神经激素戒断的作用可以推断，但不能确定。在接受4周醛固酮/盐治疗（ALDOST）的病毒症大鼠中，初步研究发现心脏和骨骼肌的转录组发生了改变，包括上调的ubiquitin特异性蛋白酶e2和下调的胰岛素生长因子(IGF)-1。停用ALDOST 4周后，体重和萎缩肌肉自然恢复，继续使用ALDOST并补充ALDO受体拮抗剂螺内酯（Spiro） 4周后，辅助恢复。假设。慢性ALDOST第4周的消耗可以通过停药、与干扰醛固酮受体结合、Ca2+超载或氧化应激的药物共同治疗、或单独使用合成代谢剂或与选择性ALDO受体拮抗剂eplerenone （Epler）联合治疗来逆转。从基因表达异常中恢复应该让我们了解每种药物的有效性和缺点。计划。我们将使用ALDOST模型（其中甲状旁腺激素介导的细胞内Ca2+超载诱导氧化应激已在临床前阶段（第1周）被证明，随后是恶病质（第4周））来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，可以随时停用。基因表达阵列使我们能够揭示导致恶病质的途径，以及每种治疗在多大程度上逆转了心脏和骨骼肌基因组、生物化学和结构的异常。目的1：表征心脏和骨骼肌慢性ALDOST临床前（第1周）和病理（第4周）阶段的生化和基因表达异常，以及在4周后停用ALDOST自然恢复的潜力；并将这种逆转与辅助恢复进行比较，当6周和8周ALDOST包括2周或4周的Spiro或Epler联合治疗时，从第4周开始。目标# 2:表征第6周和第8周ALDOST时病变心脏和骨骼肌的恢复和分子事件，以响应减轻细胞内Ca2+超载提供的辅助恢复，使用a) cinacalcet，一种重置甲状旁腺Ca2+感应受体以抑制继发性甲状旁腺功能亢进（SHPT）的拟钙化物，b)氨氯地平，一种l型Ca2+通道阻滞剂，阻止Ca2+进入SHPT设置，c)通过n -乙酰半胱氨酸消除氧化应激。抗氧化剂，从第4周开始。目的3：当在ALDOST第4周引入合成代谢剂治疗4周，使用IGF-1输注，单独或与Epler一起给药时，确定恢复的分子证据是否会出现在患病心脏和骨骼肌的转录组和结构中。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损耗或恶病质，预后不佳，被认为是不可逆转的。本研究将探讨与醛固酮/盐治疗大鼠恶病质恢复有关的分子机制，以及该方案可通过停药或药物干预实现的恢复。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。高级CHF伴

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.