Mitochondrial abnormalities of muscle tissue in mice with juvenile visceral steatosis associated with systemic carnitine deficiency

Abstract

A mouse with juvenile visceral steatosis (the JVS mouse) has been recognized as a novel animal model for systemic carnitine deficiency. We examined cardiac, skeletal and smooth muscle cells in JVS and control mice by light and electron microscopy. Cardiac and skeletal muscle cells of these mice at 4 weeks of age exhibited a ragged-red appearance after trichrome staining. Electron microscopy, demonstrated increased numbers of mitochondria and lipid droplets in the cells. Compression or distortion of the myofibril bundles, primarily due to the increased number of mitochondria, suggests the possible existence of a functional disturbance of the cardiac and skeletal muscle. In the urinary bladder, only one or two large lipid droplets and slightly increased number of mitochondria were recognized in the perinuclear region of the smooth muscle cells. At 8 weeks of age, the mouse enzyme histochemistry specific for mitochondria, such as cytochrome c oxidase and succinic dehydrogenase, and oil red O staining, confirmed further increases in the number of mitochondria and lipid droplets in the heart. However, the accumulation of these organelles in the skeletal and smooth muscle cells was no greater than that noted in JVS mice at 4 weeks of age. In the cardiac muscle cells, autolysosomes or autophagic vacuoles containing electron-dense membranous, lamellar or whorled structures closely associated with mitochondria and pseudoinclusion bodies in the nucleus were recognized, and bundles of myofibrils were buried under numerous mitochondria, suggesting the existence of disturbed contractile function in the heart of JVS mice. These results indicate that this murine strain associated with systemic carnitine deficiency exhibits a generalized mitochondrial abnormality in the muscle system especially in the heart.

Carnitine is necessary to maintain the phenotype and function of brown adipose tissue

“…Role of carnitine in brown adipocytes K Ozaki et al and display a severe carnitine deficiency and the accumulation of lipid droplets in various cells (hepatocytes, renal tubular epithelial cells, cardiac myocytes, and striated myocytes). [12][13][14]17 L-carnitine administration increases the carnitine concentration and eliminates the accumulation of lipids in the liver, heart, and skeletal muscle of JVS mice. 12,14,17,26 However, tissue carnitine levels in the heart, liver, and skeletal muscle are significantly lower than those in controls, even after L-carnitine administration.…”

“…11 The JVS phenotype is inherited in an autosomal recessive manner and is characterized by growth retardation, fatty liver, hypoglycemia, hyperammonemia, and cardiac hypertrophy. [12][13][14][15][16][17][18][19] Carnitine administration improves the characteristic symptoms of JVS mice. 15,17,18,20 Moribund JVS mice display continuous shivering, which is attributable to a decrease in heat production and an enhanced sensitivity to cold.…”

Functional Disorders of the Oxidative Phosphorylation System in the Heart Mitochondria of Mice with Juvenile Visceral Steatosis.

“…Thus, these results strongly suggest the presence of some novel heart-specific transcription/replication factors controlling the mitochondrial number, because the increase in mitochondrial number in JVS mice was observed only in the cardiac and skeletal muscle cells. 6,7) In addition, Bergeron et al reported that chronic activation of AMP-activated protein kinase (AMPK), which is caused by energetic stress by treatment with the creatine analog b-guanidinopropionic acid (b-GPA), might result in mitochondrial biogenesis in skeletal muscle. 46) They suggested that activation of AMPK also activated NRF-1, which thereby resulted in an increase in the cytochrome c content.…”

“…[2][3][4] In JVS mice, the reabsorption system of carnitine in the kidney is defective; 5) and, as a result, carnitine levels are low in the plasma, liver, skeletal muscle, and heart. 4,6,7) Recently, it was proved that primary systemic carnitine deficiency in JVS mice is caused by a missense mutation in a gene encoding the sodium ion-dependent carnitine transporter. 8,9) Horiuchi et al reported that carnitine administration corrected growth retardation and abnormal gene expression of urea-cycle enzymes and was partly effective in ameliorating the fatty liver and in suppressing the cardiac hypertrophy.…”

“…6,7) Morphological analysis has shown that the percent of myocyte volume attributable to mitochondrial volume was 66% in JVS mice and 37% in control mice and that the myocyte volume per nucleus in JVS mice was approximately 60% larger than that in control mice. 7) Thus, the mitochondrial number in the cardiac cells of JVS mice was increased approximately three-fold compared with that of control mice.…”