Patients with chronic renal failure commonly present with muscle weakness. Histological and histochemical studies demonstrate a primary myopathic disease unrelated to the polyneuropathy of chronic uremia. Several mechanisms have been suggested in the mediation of this myopathy including: 1) abnormal nutrition and reduced energy intake, 2) disturbed muscle amino acid and protein metabolism, 3) excess parathyroid hormone, and 4) an impaired vitamin D metabolism, (reduced effective levels of 1,25(OH)2D3. Based on the clinical observations of marked improvement of the myopathy in uremic patients and animals, a major role for vitamin D was suggested. The mechanism and the cellular localization by which uremia causes skeletal myopathy, and its relationship to vitamin D has not been examined systematically. Several preliminary studies show: 1) abnormal muscle histology and histochemistry in uremic animals and patients, reversible upon administration of either 25(OH)D3 or 1,25(OH)2D3, 2) reduced ATP levels in skeletal muscle of patients with uremia and improvement upon 1,25(OH)D3. On the other hand, in vivo studies in the rat and chick find no changes in skeletal muscle ATP levels and no effect of vitamin D 1,25(OH)D3 on its levels. In contrast, in vitro studies show a definite effect of 25(OH)D3 on muscle ATP levels. Thus, the cellular mechanisms mediating uremic myopathy and the relationship to vitamin D metabolites are not clear. Since vitamin D 1,25(OH)D3 influences the metabolism of cell energetics, membrane phospholipids and contractile proteins, a possible mechanism for the uremic myopathy and the therapeutic effects of the vitamin is suggested. The goals of this proposal are: 1) to examine skeletal muscle functions and all steps of cellular energy metabolism in uremia, 2) to evaluate skeletal muscle cell membranes (sarcolemal sarcoplasmic reticulum, mitochondria) functional and biochemical integrity, 3) to examine skeletal muscle contractile proteins, 4) investigate whether the administration of vitamin D (25OH)D3 or 1,25(OH)2D3 can reverse such abnormal findings, and localize its cellular therapeutic effects.
