Kondo Hibernation Control Project
Kanagawa Academy of Science and Technology
Mitsubishi Kasei Institute of Life Sciences
Machida, Tokyo 194, Japan
n mammals, a body temperature is regulated at a high, constant level. The lowering body temperature induces dysfunction of various physiological systems in the body resulting in death. However, mammalian hibernators, such as chipmunks and ground squirrels, undergo an extreme hypothermia (near 0°C) without death during hibernation. A life is sustained consuming much less energy by the depressing metabolic activity. In this period, the body is protected against a low body temperature and has a tolerance to harmful events, such as ischemia, bacterial infection and irradiation. Furthermore, from the similarity of hibernation to sleep and the depression of aging during hibernation, it is considered that mechanisms of the physiological defense in the body are involved in hibernation. Although a hibernation mechanism contains exciting possibilities that will develop into the applications in the life science fields, a mechanism of hibernation is not understood. However, the facts that hibernation is regulated by an endogenous circannual rhythm and is the inherited character specific for hibernators reveal existence of a control system of hibernation regulated by genes specific for hibernation.
In our recent studies, a novel protein complex specific for hibernation has been found in the blood of chipmunks, a typical mammalian hibernator. This complex was composed of four proteins. Three of them (HP-20, -25, -27) were structurally similar and formed a collagen-like triple helix in N-terminal regions stabilized by interchain disulfide bonds among them. This complex (HP-20C) was further associated with the fourth protein (HP-55) which is highly homologous to alpha 1-antitrypsin, a protease inhibitor. The associates (HPc) were markedly reduced prior to, and during, hibernation. The expression of genes encoding HP-20s in liver was depressed in the same periods. Such changes in HPc in the blood were completely synchronous with hibernation which was repeated circannually under constant cold laboratory conditions for several years. Similar circannual changes in HPc were observed even in animals kept nonhibernating under constant warm laboratory conditions. In these animals, hibernation was induced by exposure to cold only when HPc was lowered. These results indicate existence of an endogenous circannual mechanism controlling hibernation. This mechanism functions automatically without environmental changes, and regulates the production of HPs. Furthermore, in the immunochemical analysis of HPs in several species of rodents using antibodies to HPs, HPs were detected in hibernators (ground squirrels and woodchuck), but not in nonhibernators (tree squirrels, rat and mouse), indicating a genetical specificity of HPs for a hibernation character. The present discovery of HP will allow us to clarify not only a signal transduction for controlling hibernation but also a physiological system for resistance to cold injury in hibernating mammals.
