Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia

Abstract

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5' AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: 5-aminoimidazole-4-carboxamide ribonucleotide; ACE; AICAR; AMP-activated kinase; AMPK; AT1R; AgRP; Ang II; Angiotensin II; CHF; CRH; Cachexia; Congestive heart failure; ERK; ESRD; GR; IGF-1; IL-6; IRS-1; MAPK; Npy; PI3K; POMC; ROS; SAA; Skeletal muscle; TGF-β; TNF-α; TRH; UPS; agouti-related protein; angiotensin II; angiotensin II type 1 receptor; angiotensin-converting enzyme; congestive heart failure; corticotropin-releasing hormone; end-stage renal disease; extracellular signal-regulted kinase; glucocorticoid receptor; insulin receptor substarte; insulin-like growth factor-1; interleukin-6; mTOR; mammalian target of rapamycin; mitogen-activated kinase; neuropeptide Y; phosphoinositide 3-kinase; proopiomelanocortin; reactive oxygen species; serum amyloid A; thyrotropin-releasing hormone; transforming growth factor-β; tumor necrosis factor-α; ubiquitin proteasome system.