Mechanisms of Cachexia in Chronic Disease States

Abstract

Sarcopenia and cachexia are muscle wasting syndromes associated with aging and with many chronic diseases, such as congestive heart failure (CHF), diabetes, cancer, chronic obstructive pulmonary disease and chronic kidney disease (CKD). While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme inhibitor treatment improves weight loss. It was found that Ang II infusion in rodents leads to skeletal muscle wasting. Ang II increases cytokines and circulating hormones, such as tumor necrosis factor-α, interleukin-6, serum amyloid-A and glucocorticoids, which regulate muscle protein synthesis and degradation. Ang II–induced muscle wasting is caused by alterations in insulin-like growth factor-1 signaling, enhanced muscle protein breakdown via the ubiquitin-proteasome system and decreased appetite resulting from the downregulation of hypothalamic orexigenic neuropeptides, such as Npy and orexin. Ang II also inhibits 5′ adenosine monophosphate–activated protein kinase activity and disrupts normal energy balance via the activation of 5′ adenosine monophosphate–activated protein kinase phosphatase PP2Cα. Furthermore, Ang II inhibits skeletal muscle stem (satellite) cell proliferation, leading to lowered muscle regenerative capacity. Distinct satellite cell angiotensin receptor subtypes have different effects on different stages of differentiation and are critical for the regulation of muscle regeneration. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states, and it is a promising target for the treatment of muscle atrophy in patients with diseases such as CHF and CKD.