Although rachitic/osteomalacic myopathy caused by impaired vitamin D actions has long been described, the molecular pathogenesis remains elusive. To determine physiological roles of vitamin D actions through vitamin D receptor (VDR) in skeletal muscle development, we examined skeletal muscle in VDR gene deleted (VDR -/-) mice, an animal model of vitamin D-dependent rickets type II, for morphological changes and expression of myoregulatory transcription factors and myosin heavy chain isoforms. We found that each muscle fiber was small and variable in size in hindlimb skeletal muscle from VDR -/- mice, although overall myocyte differentiation occurred normally. These abnormalities were independent of secondary metabolic changes such as hypocalcemia and hypophosphatemia, and were accompanied by aberrantly high and persistent expression of myf5, myogenin, E2A, and early myosin heavy chain isoforms, which are normally down-regulated at earlier stages. Moreover, treatment of VDR-positive myoblastic cells with 1,25(OH)2D3 in vitro caused down-regulation of these factors. These results suggest that VDR plays a physiological role in skeletal muscle development, participating in temporally strict down-regulation of myoregulatory transcription factors. The present study can form a molecular basis of VDR actions on muscle and should help further establish the physiological roles of VDR in muscle development as well as pharmacological effects of vitamin D on muscle functions.

Abstract-Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43Ϯ8.9% (meanϮSEM) from the values obtained before GC therapy (130Ϯ14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5Ϯ3.3% of control values by 10 Ϫ7 mol/L dexamethasone (DEX) treatment (PϽ0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (PϽ0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess. Key Words: glucocorticoid Ⅲ reactive oxygen species Ⅲ nitric oxide Ⅲ vascular endothelial function G lucocorticoid (GC) has being used widely for the treatment of patients with various disorders including autoimmune diseases, allergic diseases, and lymphoproliferative disorders. It has been well known, however, that GC therapy using prednisolone, methylprednisolone, or dexamethasone (DEX) is often limited by several adverse reactions associated with GC excess. 1,2 GC excess exhibits a variety of symptoms and signs, including truncal obesity with moon face, striae, hirsutism, cataract, osteoporosis, myopathy, diabetes mellitus, immunosuppression, and cardiovascular disorders such as hypertension and atherosclerosis. 3 Among these, cardiovascular complications are one of the important factors for predicting the morbidity and mortality of patients with GC excess. 3 Plasma volume expansion due to sodium retention plays a minor role, 1,2,4 and increased peripheral vascular resistance due in part to an increased pressor response to catecholamines and angiotensin II is shown to play a major role in the pathogenesis of hypertension induced by GC excess. 1,2,5 However, the molecular mechanism whereby GC excess causes the increase in vascular resistance remains unclear.Vascular endothelial cells regulate vascular tone through the release of a variety of relaxing and contracting factors that modulate the contractile activity of vascular smooth muscle cells. 6,7 Nitric oxide (NO), an endothelial cell-derived relaxing factor, is thought to be the most important vaso...

We describe a novel function of parkin, a RING protein, which is elaborately involved in mitochondrial biogenesis. Parkin was located within the mitochondrial organelle of proliferating cells. Anti-proliferative treatments released parkin from mitochondria to cytosol. Results of pharmacological treatments indicate that parkin was released from mitochondria when permeability transition pore was opened. The extra-mitochondrial localization was also observed in differentiated cells. In proliferating cells, transcription and replication of mitochondrial DNA was enhanced by parkin overexpression and attenuated by parkin suppression with siRNA. Parkin was associated with mitochondrial transcription factor A (TFAM) and enhanced TFAM-mediated mitochondrial transcription. These results indicate that parkin is involved in the regulation of mitochondrial transcription/replication other than the ubiquitin-mediated protein degradation system in proliferating cells.

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