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.

Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia

“…The loss of cardiac mass in chronic diseases such as cancer, heart failure, and obstructive pulmonary disease has been extensively reported [29][30][31][32][33][34], but the mechanisms responsible for this process are only partially elucidated [35]. In rats implanted with Walker-256 tumours -a carcinosarcoma of the mammary glands of pregnant rats [36] -tumour growth occurred quickly, causing progressive weight loss and leading to cachexia syndrome within only5 days.…”

Cardiac cachexia and muscle wasting: definition, physiopathology, and clinical consequences

“…27 One of the most important pathways responsible for intracellular degradation of striated muscle proteins is the ubiquitin-proteasome system. [28][29][30] During ubiquitination, damaged cytosolic proteins are linked to ubiquitin molecules and targeted toward the proteasome, where they are cleaved into short peptides and aminoacids. 31 In heart failure, immunological and neurohormonal activation, as well as increased reactive oxygen species levels, stimulate nuclear factor-κB, which activates the ubiquitin proteasome system.…”

“…27,48 Experimental studies have shown that AII can contribute to muscle wasting by increasing protein breakdown, reducing protein synthesis, and inhibiting muscle regenerative processes. 28,49 More recently, the role of neurohormonal activation has also been evaluated in noncardiac cachexia. In liver cancer rats, β-blocker or aldosterone antagonism has increased survival and improved cancer-induced cardiac dysfunction.…”

Why Age Matters: Inflammation, Cancer and Hormones in the Development of Sarcopenia

“…Mechanistically, reactive oxygen species and IGF-1 lead to apoptosis and protein degradation and therefore muscle wasting [50,51], which reveals the Angiotensin IIInfusion as an uncommon model for muscle wasting.…”

“…In these KPC-mice, pancreatic adenocarcinoma develops with median survival of five months [13]. Underlying molecular mechanisms involve increased levels of Atrogin-1 and MuRF1 [49][50][51][52].…”