Nutritional Approach to Cancer Cachexia: A Proposal for Dietitians

Cachexia is one of the most common, related factors of malnutrition in cancer patients. Cancer cachexia is a multifactorial syndrome characterized by persistent loss of skeletal muscle mass and fat mass, resulting in irreversible and progressive functional impairment. The skeletal muscle loss cannot be reversed by conventional nutritional support, and a combination of anti-inflammatory agents and other nutrients is recommended. In this review, we reviewed the effects of nutrients that are expected to combat muscle loss caused by cancer cachexia (eicosapentaenoic acid, β-hydroxy-β-methylbutyrate, creatine, and carnitine) to propose nutritional approaches that can be taken at present. Current evidence is based on the intake of nutrients as supplements; however, the long-term and continuous intake of nutrients as food has the potential to be useful for the body. Therefore, in addition to conventional nutritional support, we believe that it is important for the dietitian to work with the clinical team to first fully assess the patient’s condition and then to safely incorporate nutrients that are expected to have specific functions for cancer cachexia from foods and supplements.

Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training

Cachexia is a multifactorial syndrome that presents with, among other characteristics, progressive loss of muscle mass and anti-cardiac remodeling effect that may lead to heart failure. This condition affects about 80% of patients with advanced cancer and contributes to worsening patients’ tolerance to anticancer treatments and to their premature death. Its pathogenesis involves an imbalance in metabolic homeostasis, with increased catabolism and inflammatory cytokines levels, leading to proteolysis and lipolysis, with insufficient food intake. A multimodal approach is indicated for patients with cachexia, with the aim of reducing the speed of muscle wasting and improving their quality of life, which may include nutritional, physical, pharmacologic, and psychological support. This review aims to outline the mechanisms of muscle loss, as well as to evaluate the current clinical evidence of the use of physical exercise in patients with cachexia.

Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation

Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.

LPS induces rapid increase in GDF15 levels in mice, rats and humans but is not required for anorexia in mice

Growth differentiation factor 15 (GDF15), a TGFβ superfamily cytokine, acts through its receptor, GDNF-family receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiologic responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat and human. However, we did not detect differences in LPS induced anorexia between WT and GDF15KO or GFRALKO mice. Further, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.