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 (ACE) inhibitor treatment improves weight loss. We 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 downregulation of hypothalamic orexigenic neuropeptides such as Npy and orexin. Ang II also inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance via activation of AMPK 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 regulation of muscle regeneration. These data suggest that the renin-angiotensin system (RAS) plays a critical role in mechanisms underlying cachexia in chronic disease states, and is a promising target for the treatment of muscle atrophy in patients with diseases such as CHF and CKD.

Neuromuscular electrical stimulation of the thighs in cardiac patients with implantable cardioverter defibrillators

“…Cardiac cachexia is a serious complication of CHF with a high morbidity and mortality, and is characterized by significant weight loss and muscle wasting [1, 2]. CHF-related muscle wasting is the result of an ongoing imbalance in the activation of anabolic and catabolic pathways [3, 5, 6]. This imbalance is caused by a series of immunologic, metabolic, and neuro-hormonal processes [2, 6, 7].…”

The wasting continuum in heart failure: from sarcopenia to cachexia

“…Only few studies were done in patients with HF even though exercise capacity has been improved by several means. A thorough understanding of molecular pathways involved in the process of muscle wasting is crucial to identify targets for therapeutic interventions (27,28) . Cachexia therapies, on the other hand, are aimed primarily at increasing body weight and thus at increasing muscle and fat tissue.…”

miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice

“…In resting muscle, satellite cells are mostly quiescent; however, in response to stress or injury, these cells are activated, proliferate, and undergo differentiation to repair damaged muscle or selfrenewal to replenish the quiescent cell pool [10][11][12]. Reduced satellite cell function has been observed in patients with chronic diseases, including cancer-induced cachexia and diabetes [13,14]. Moreover, reduced muscle stem cell function may be a potentially important mechanism in the pathogenic development of age-related sarcopenia [15,16].…”