Reversing Cachexia

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Wasting of skeletal muscle is common in a number of diseases, including sepsis, severe injury, renal failure, diabetes, and cancer. Muscle atrophy leads to general muscle weakness (asthenia), impairment of normal activities, and eventually death through respiratory failure. Muscle loss is part of the syndrome of cachexia and arises through a combination of hypoanabolism, together with increased catabolism of myofibrillar proteins, particularly myosin. Cachexia affects ∼80% of patients with advanced cancers and accounts for ∼25% of deaths, but current treatments for muscle atrophy are limited. Many studies show that the ubiquitin-proteasome proteolytic pathway plays a major role in the degradation of muscle proteins during cachexia (Lecker et al., 1999). Expression of two muscle-specific ubiquitin ligases is essential for ubiquitination and subsequent degradation of myofibrillar proteins. These are MuRF1, whose substrates include myosin in muscle and troponin 1 in heart (Clarke et al., 2007), and atrogin-1/MAFbx, which targets the eukaryotic initiation factor 3 subunit 5 that induces expression of muscle structural proteins and boosts muscle growth (hypertrophy) (Lagirand-Cantaloube et al., 2008). Apoptosis may also be involved in muscle wasting, and depression of protein synthesis and stem cell quiescence are also known to lead to hypoanabolism. In this issue, Zhou et al. (2010) report the identity of a new potential therapeutic target, the activin type-2 receptor (ActRIIB), for treating muscle wasting. They show in several mouse models of cachexia that blocking ActRIIB with a decoy receptor not only counters the wasting process in skeletal muscle and heart but also is associated with increased survival.

A number of factors have been implicated in muscle wasting, including cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6, and interferon-γ, as well as tumor factors such as proteolysis-inducing factor and glucocorticoids (Tisdale, 2009). Myostatin, a member of the TGF-β superfamily, plays an important role in glucocorticoid-induced muscle atrophy (Gilson et al., 2007). Myostatin is a negative regulator of muscle growth and, together with activin, another member of the TGF-β family, is thought to be responsible for the development of cachexia in mice lacking the hormone inhibin (which antagonizes activin action) (Matzuk et al., 1994). Both myostatin and activin bind to ActRIIB, a high-affinity activin type-2 receptor in muscle, to initiate a signaling cascade leading to increased expression of atrogin-1 and MuRF1 and increased degradation of myofibrillar proteins through the ubiquitin-proteasome pathway (Figure 1).
https://www.sciencedirect.com/science/a ... 7410008998

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Abstract
Cancer cachexia is a metabolic syndrome that can be present even in the absence of weight loss ('precachexia'). Cachexia is often compounded by pre-existing muscle loss, and is exacerbated by cancer therapy. Furthermore, cachexia is frequently obscured by obesity, leading to under-diagnosis and excess mortality. Muscle wasting (the signal event in cachexia) is associated not only with reduced quality of life, but also markedly increased toxicity from chemotherapy. Many of the primary events driving cachexia are likely mediated via the central nervous system and include inflammation-related anorexia and hypoanabolism or hypercatabolism. Treatment of cachexia should be initiated early. In addition to active management of secondary causes of anorexia (such as pain and nausea), therapy should target reduced food intake (nutritional support), inflammation-related metabolic change (anti-inflammatory drugs or nutrients) and reduced physical activity (resistance exercise). Advances in the understanding of the molecular biology of the brain, immune system and skeletal muscle have provided novel targets for the treatment of cachexia. The combination of therapies into a standard multimodal package coupled with the development of novel therapeutics promises a new era in supportive oncology whereby quality of life and tolerance to cancer therapy could be improved considerably.

https://www.ncbi.nlm.nih.gov/m/pubmed/23207794/

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Treatment of Cachexia in Oncology


Abstract

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful.

Keywords: Cachexia, Oncology, Treatment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012235/