No abstract

Microperoxidase (MP, a peptide tracer) was intravenously injected into rats after six days of tooth movement by the Waldo method. Bone resorption was seen along the distal bone surface of the inter-radicular septum of the upper first molar, and tooth root resorption occurred along the mesial and distal surfaces of the distal root of the same molar. Odontoclasts were smaller in size and numbers than osteoclasts, but had the same organelles [multiple nuclei, ruffled borders (RB), clear zones, vacuoles, mitochondria, and specific granules] as osteoclasts. MP was deposited on the resorbed area through the clear zone and was transported into the vacuoles along the channels of the RB. The uptake of MP by odontoclasts was small, compared with that by osteoclasts. Collagen fibrils were found in the channels of the RB but were not detected in the vacuoles. Instead, filament-like structures were seen in the vacuoles and were located very near the collagen fibrils in the channels. Fibroblasts outside the resorbed lacunae had endocytosed collagen. In contrast, some cells close to odontoclasts (osteoclasts) in the dentin (bone)-resorbed lacunae had not endocytosed any collagen fibrils. These findings suggest (1) that odontoclasts resorb the dentin or cementum just as osteoclasts do in bone resorption, (2) that the resorbed area connects with the extracellular spaces of the odontoclasts or osteoclasts, and (3) that the organic components (e.g., collagen fibrils) of dentin or cementum are endocytosed through the channels of the RB in the same manner as that for MP. However, the endocytotic ability of odontoclasts appears inferior to that of osteoclasts.

It is known that the catabolism of branched-chain amino acids (BCAAs) in skeletal muscle is suppressed under normal and sedentary conditions but is promoted by exercise. BCAA catabolism in muscle tissues is regulated by the branched-chain α-keto acid (BCKA) dehydrogenase complex, which is inactivated by phosphorylation by BCKA dehydrogenase kinase (BDK). In the present study, we used muscle-specific BDK deficient mice (BDK-mKO mice) to examine the effect of uncontrolled BCAA catabolism on endurance exercise performance and skeletal muscle energy metabolism. Untrained control and BDK-mKO mice showed the same performance; however, the endurance performance enhanced by 2 weeks of running training was somewhat, but significantly less in BDK-mKO mice than in control mice. Skeletal muscle of BDK-mKO mice had low levels of glycogen. Metabolome analysis showed that BCAA catabolism was greatly enhanced in the muscle of BDK-mKO mice and produced branched-chain acyl-carnitine, which induced perturbation of energy metabolism in the muscle. These results suggest that the tight regulation of BCAA catabolism in muscles is important for homeostasis of muscle energy metabolism and, at least in part, for adaptation to exercise training.

The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1(ko) /H2(ko) ) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1(ko) /H2(eko) ) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1(ko) /H2(ko) phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1(ko) /H2(eko) embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency.