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. 2013 Oct;45(10):2322-32.
doi: 10.1016/j.biocel.2013.05.035. Epub 2013 Jun 13.

Molecular Mechanisms and Signaling Pathways of Angiotensin II-induced Muscle Wasting: Potential Therapeutic Targets for Cardiac Cachexia

Free PMC article

Molecular Mechanisms and Signaling Pathways of Angiotensin II-induced Muscle Wasting: Potential Therapeutic Targets for Cardiac Cachexia

Tadashi Yoshida et al. Int J Biochem Cell Biol. .
Free PMC article


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.


Figure 1
Figure 1. Molecules and signaling pathways involved in Ang II-induced skeletal muscle atrophy
Ang II increases ROS in skeletal muscle via AT1R and NADPH oxidase dependent mechanisms. Increased ROS activates caspase-3 and the NF-κB pathway, which result in activation of the UPS and protein degradation. Ang II also suppresses IGF-1 signaling via serine phosphorylation of IRS-1 and PI3K, resulting in decreased protein synthesis. Local production of IGF-1 is decreased by Ang II and protein synthesis is attenuated. Systemic Ang II increase causes elevation of TNF-α, IL-6, SAA, glucocorticoid and myostatin. TNF-α induces protein degradation via activation of the NF-κB pathway. IL-6 and SAA synergistically activate SOCS-3, and prevent IGF-1 signaling. GR competitively prevents IRS-1 and PI3K association. Myostatin inhibits Akt phosphorylation, which results in decreased protein synthesis and increased protein degradation.
Figure 2
Figure 2. Multiple mechanisms involved in Ang II-induced muscle wasting: potential mechanism of cardiac cachexia
In heart failure patients, there is an increase of Ang II. Increased Ang II causes a reduction of IGF-1 and an increase in glucocorticoids, IL-6, SAA, TNF-α and myostatin, all of which result in muscle wasting. See figure 1 for detailed signaling pathways involved. Ang II also acts on hypothalamic neurons to reduce appetite, via regulation of orexigenic/anorexigenic neuropeptides such as Npy, Orexin and CRH. Ang II may regulate satellite cell function and prevent skeletal muscle regeneration. The combination of Ang II-induced muscle wasting, reduced food intake and altered muscle regeneration lead to the development of cachexia.

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