Systemic zinc redistribution and dyshomeostasis in cancer cachexia

Cachexia affects up to two thirds of all cancer patients and is a significant cause of morbidity and mortality. It is a complex metabolic syndrome associated with the underlying illness and characterized by loss of skeletal muscle tissue with or without loss of fat mass. Cachexia’s other prominent clinical symptoms include anorexia, systemic inflammation, pediatric growth failure, and hypogonadism. The relationship between the symptoms of cancer cachexia and the underlying illness is unclear, and there is an urgent need for a better understanding of the pathophysiology of this syndrome. Normal Zn metabolism is often disrupted in cancer patients, but the possible effects of systemic Zn dyshomeostasis in cachexia have not been investigated. We propose that the acute phase response can mediate Zn redistribution and accumulation in skeletal muscle tissue and contribute to the activation of the ubiquitin–proteasome pathway that regulates protein catabolism. This chronic redistribution deprives Zn from other tissues and organs and compromises critical physiological functions in the body. The cardinal symptoms of Zn deficiency are anorexia, systemic inflammation, growth failure in children, and hypogonadism. These symptoms also prominently characterize cancer cachexia suggesting that the role of systemic Zn dyshomeostasis in cachexia should be investigated

Beneficial effect of an essential fatty acid deficient diet in nzb/nzw f1 mice.

New Zealand Black by White (B/W) hybrid mice spontaneously develop a disease similar to systemic lupus erythematosus (SLE). Subepidermal immunoglobulin deposits (Se-Ig) and antibodies to double-standed DNA (anti-dsDNA) develop in aging mice. Death from glomerulonephritis occurs at 8 to 12 mo. Previous findings suggest that epidermal DNA:anti-dsDNA complexes form in situ since Se-Ig correlates with anti-ds DNA and Se-Ig accumulation is augmented by increased epidermal proliferation (presumably due to enhanced epidermal DNA release). Since essential fatty acid (EFA) deficiency is known to increase epidermal proliferation we have studied the effect of an essential fatty acid deficient EFA-d diet on: (1) Se-Ig, (2) anti-dsDNA, and (3) survival. Ten-mo B/W mice on an EFA-d diet were compared with 14 controls on a calorically equivalent standard diet. Both groups were initiated on their diets at 2 mo of age. Only female mice were used. All were weighed weekly; tested for anti-ds DNA (Crithidia luciliae assay) each month; and biopsied for direct immunofluorescence (IF) staining of skin at 6, 7.5, 9, 10.5, and 12 mo. Tissue (skin and kidney) was also obtained for light and IF microscopy. Weights in the 2 study groups were essentially identical. All disease manifestations examined were strikingly altered in the EFA-d animals. Only 2 of 14 (14%) control animals survived to 9 mo and both had anti-dsDNA and Se-Ig. In contrast, 8 of 10 (80%) EFA-d mice were alive at 9 mo and none had anti-dsDNA or Se-Ig. The kidneys from EFA-d mice at 10 mo were normal; however, all kidneys from 7 to 9 mo control mice were abnormal by both light and IF microscopy. Eight of the 10 EFA-d mice were alive at 10 mo. None had Se-Ig but one had anti- dsDNA