Liver and muscle protein metabolism in cachexia

Abstract

Up to 50% of cancer patients suffer from progressive weight loss (cachexia). Cachexia is induced by proinflammatory mediators (cytokines), induced by the tumor’s presence. These cytokines induce so-called acute phase protein synthesis by the liver, followed by skeletal muscle protein breakdown. Skeletal muscle protein breakdown seems to serve for providing amino acids (AA) for acute phase protein synthesis in the liver. The net effect of cytokines is a negative protein balance in the skeletal muscle, leading to decreased volume and mass, and ultimately in decreased function of muscles. If missed in treatment, cachexia inevitably leads to death due to catabolism of respiratory and cardiac muscle tissue, resulting in cardiac and respiratory failure. Due to these complications cachexia has been estimated to be responsible for more than 20% of overall deaths in cancer patients. In his thesis, Stephan Peters (1971) proposes a nutritional intervention to inhibit cancer cachexia. The nutrition for the cancer patient should provide a combination of nutritional components that induce skeletal muscle protein synthesis on the one hand inhibit the cytokine response on the other hand. These are the conclusions of the PhD thesis of Stephan Peters. His PhD defense will take place on December 17th in the Academiegebouw in Utrecht. Protein balance between the liver and skeletal muscle in cancer cachexie Peters shows that cytokines induce acute phase protein synthesis in the liver. Under normal circumstances, these proteins are involved in recovery from inflammation and injury. However, although these proteins are produced in cancer, they do not seem to play a role in reducing tumor volume. This results in a prolonged protein production by the liver, followed by skeletal muscle protein breakdown. Muscle breakdown ultimately leads to weakness of the patient and breakdown of respiratory muscles. Hence, muscle breakdown is associated with shorter survival time of the patient. New explanation skeletal muscle breakdown Besides protein accretion, muscle growth is dependent on the uptake of so-called satellite cells (progenitor cells of muscles) in the muscle fibers. It is shown that cytokines inhibit uptake of satellite cells in the muscle fibers, leading to inhibition of muscle growth or muscle breakdown. Optimal nutrition for the cancer cachectic patient Based on his research in both liver and muscle cells, followed by a cancer cachexia mouse model, Peters concludes that an optimal nutrition for the cancer cachectic patient should comprise of (i) enough protein enriched with leucine to induce protein synthesis in the skeletal muscle. In addition, (ii) the nutrition should contain components (like e.g., fish-oil) that inhibit cytokine production, leading to uptake of satellite cells in the muscle. Only such combination can lead to inhibition of the cancer cachectic process by nutrition.