Studies on Brown FK. IV. Cytopathic effects of Brown FK on cardiac and skeletal muscle in the rat

Abstract

Administration of two or three massive (1 g/kg) oral doses of Brown FK to rats induced a myopathy in cardiac and skeletal muscles characterized by multiple vacuoles about 1–2 μ in diameter. Ultrastructurally, these were shown to consist of areas of fibrillolysis, affecting initially the A-band. Histochemically, the myopathy was accompanied by a moderate increase in acid-phosphatase activity and by a loss of phosphorylase activity. Subsequently, complete lysis of the affected fibres ensued. In the heart, lysis was followed by macrophage invasion and fibroblastic proliferation, and in skeletal muscle, by regeneration. The occurrence of lipofuscin in muscle fibres and in macrophages was scanty and erratic. When Brown FK was given in the diet at a level of 2%, fibrillolysis and an increase in the number and electron-density of lysosomes was observed ultrastructurally during wk 2–3 of the test. These changes were accompanied by a marked elevation of histochemically-demonstrable acid phosphatase. Progressive deposition of lipofuscin was the principal pathological feature during wk 3–12. Initial damage to the A- and I-bands in both cardiac and skeletal muscle distinguishes the Brown FK myopathy from that known to be produced by high doses of corticosteroids, thyroxine, chloroquine or plasmocid, from ischaemic damage and from muscle damage resulting from deprivation of potassium, calcium or magnesium. The lysosomal changes and accumulation of lipofuscin are suggestive of primary lysosomal damage which may be responsible, at least in part, for the pathological effects observed.