A MOUSE MODEL FOR MITOCHONDRIAL MYOPATHY AND CARDIOMYOPATHY RESULTINGFROM A DEFICIENCY IN THE HEART MUSCLE ISOFORM OF THE ADENINE-NUCLEOTIDE TRANSLOCATOR/

In an attempt to create an animal model of tissue-specific mitochondri al disease, we generated 'knockout' mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1). Histological a nd ultrastructural examination of skeletal muscle from Anti null mutan ts revealed ragged-red muscle fibers and a dramatic proliferation of m itochondria, while examination of the heart revealed cardiac hypertrop hy with mitochondrial proliferation. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant 1 mutant adults also had a resting serum lactate level fourfold higher than that of controls, indicative of metabolic acidosis. Significantl y, mutant adults manifested severe exercise intolerance. Therefore, An ti mutant mice have the biochemical, histological, metabolic and physi ological characteristics of mitochondrial myopathy and cardiomyopathy.