MYOPATHY IN VITAMIN-E-DEFICIENT RATS - MUSCLE-FIBER NECROSIS ASSOCIATED WITH DISTURBANCES OF MITOCHONDRIAL-FUNCTION

Vitamin E deficiency in rats gives rise to a neuromuscular syndrome th at includes a peripheral neuropathy as well as generalised muscle wast ing and weakness. This is probably related to damage by oxygen-derived free radicals. In the present study, histological examination of lowe r limb muscles showed widespread myopathic changes which included the presence of amorphous electron-dense inclusions and tubular aggregates in muscle fibres and muscle fibre necrosis. Histochemical observation s suggested a reduction in the activity of oxidative enzymes. The mito chondria showed nonspecific degenerative changes on electron microscop y; no paracrystalline inclusions were observed. Polarographic analysis of isolated muscle mitochondria revealed statistically significant de creases in oxygen utilisation rates with both NADH and FADH(2)-linked substrates. In confirmation of a generalised respiratory chain abnorma lity, enzymatic analyses revealed decreases in the activities of compl exes I, II/III and IV, although only the decreases in complexes I and IV activities were statistically significant. Measurements of membrane fluidity showed that this is reduced in mitochondria from vitamin E d eficient rats, indicating reduced stability of their membranes. The re spiratory-control ratio, derived from the polarographic results, was a lso reduced in mitochondria from vitamin E deficient animals, suggesti ng membrane damage. An altered lipid environment, possibly secondary t o a higher level of lipid peroxidation, could result in the inhibition of complexes I and IV. This could also be caused by oxidative damage to the complexes or to mitochondrial DNA. The preservation of citrate synthase activity is against any generalised defect of mitochondrial f unction. The question as to whether these defects of mitochondrial res piratory chain function are responsible for the muscle fibre damage an d necrosis requires further investigation.