We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and from other more hypoxia sensitive systems. We propose that the response of hypoxia tolerant systems to oxygen lack occurs in two phases (defense and rescue). The first lines of defense against hypoxia include a balanced suppression of ATP-demand and ATP-supply pathways; this regulation stabilizes (adenylates) at new steady-state levels even while ATP turnover rates greatly decline. The ATP demands of ion pumping are down-regulated by generalized "channel" arrest in hepatocytes and by "spike" arrest in neurons. Hypoxic ATP demands of protein synthesis are down-regulated probably by translational arrest. In hypoxia sensitive cells this translational arrest seems irreversible, but hypoxia-tolerant systems activate "rescue" mechanisms if the period of oxygen lack is extended by preferentially regulating the expression of several proteins. In these cells, a cascade ofprocesses underpinning hypoxia rescue and defense begins with an oxygen sensor (a heme protein) and a signaltransduction pathway, which leads to significant gene-based metabolic reprogramming-the rescue process-with maintained down-regulation of energy-demand and energy-supply pathways in metabolism throughout the hypoxic period. This recent work begins to clarify how normoxic maintenance ATP turnover rates can be drastically (10-fold) down-regulated to a new hypometabolic steady state, which is prerequisite for surviving prolonged hypoxia or anoxia. The implications of these developments are extensive in biology and medicine. energy turnover supplies the greatest protection against, and hence, advantage in, hypoxia. The immense advantage of this defense strategy is widely appreciated by many biologists (4, 5, 11-13). In one of his last personal communications to one of the authors (P.W.H.), the great comparative physiologist Kjell Johansen referred to this strategy as "turning down to the pilot light" and he, like many earlier workers, was acutely aware of its relative importance. Although recognized as a kind of hallmark of reversible entry into and return from states of severe 02 deprivation, a number of unexplained problems have remained. In particular, it has not been clear (i) how cells/ tissues "know" when to turn on their hypoxia defense mechanisms, (ii) which pathways of ATP demand and ATP supply are down-regulated or by how much, (iii) how membrane electrochemical gradients are stabilized, and (iv) what geneexpression and protein-expression level adjustments are involved in hypoxic reorganization of cell structure and function. Recent studies of a well-known vertebrate "facultative anaerobe," the aquatic turtle, used brain cortical slices to probe electrophysiological properties of neurons under anoxia (16)(17)(18)(19) and isolated liver hepatocytes to probe cell level biochemical responses to anoxia (20)(21)(22)(23)(24). When integrated with ...

The power function of basal metabolic rate scaling is expressed as aM(b), where a corresponds to a scaling constant (intercept), M is body mass, and b is the scaling exponent. The 3/4 power law (the best-fit b value for mammals) was developed from Kleiber's original analysis and, since then, most workers have searched for a single cause to explain the observed allometry. Here we present a multiple-causes model of allometry, where the exponent b is the sum of the influences of multiple contributors to metabolism and control. The relative strength of each contributor, with its own characteristic exponent value, is determined by the control contribution. To illustrate its use, we apply this model to maximum versus basal metabolic rates to explain the differing scaling behaviour of these two biological states in mammals. The main difference in scaling is that, for the basal metabolic rate, the O(2) delivery steps contribute almost nothing to the global b scaling exponent, whereas for the maximum metabolic rate, the O(2) delivery steps significantly increase the global b value.

No abstract

During oxygen limitation in animals, glucose can be fermented via several metabolic pathways varying in energetic efficiency and leading to various end products (such as lactate, alanopine, octopine, succinate, or propionate). Because of opposite pH dependencies of proton production by fermentation and by hydrolysis of adenosine triphosphate formed in the fermentation, the total number of moles of protons generated is always two per mole of the fermentable substrate. However, two and three times more adenosine triphosphate can be turned over per mole of protons produced in succinate and propionate fermentations, respectively, than in lactate fermentation.

Some aspects of the biochemistry of sockeye salmon (Oncorhynchns nerka) were investigated during spawning migration in the Fraser River, B.C. Studies included measurements of the activities of metabolic enzymes, protein content, and free amino acid concentrations in various tissues. In white muscle, soluble and insoluble protein decreased by 70% during migration and the activities of most of the enzymes studied showed a similar pattern. In contrast, the activities of cathepsin D (EC 3.4.23.5) and carboxypeptidase A (EC 3.4.12A.1) increased considerably, whereas the activities of alanine aminotransferase (EC 2.6.1.2) and malic enzyme (EC 1.1.1.40) were unchanged during migration. In red muscle and heart there was little change in either protein levels or enzyme activities, with the exception of glucose-6-phosphate dehydrogenase (EC 1.1.1.4), which increased threefold to sixfold. In liver, the activities of metabolic enzymes and the levels of soluble protein decreased, whereas proteolytic enzyme activities increased slightly during migration.It is concluded that white muscle is the primary source of the amino acids utilized during migration. A model is proposed to account for the fate of the amino acids released by proteolysis in white muscle. It is suggested that most of the amino acids are collected as alanine and transported to other tissues in this form.

. Seasonal dynamics of flight muscle fatty acid binding protein and catabolic enzymes in a migratory shorebird. Am J Physiol Regulatory Integrative Comp Physiol 282: R1405-R1413, 2002; 10.1152/ ajpregu.00267.2001.-We developed an ELISA to measure heart-type fatty acid binding protein (H-FABP) in muscles of the western sandpiper (Calidris mauri), a long-distance migrant shorebird. H-FABP accounted for almost 11% of cytosolic protein in the heart. Pectoralis H-FABP levels were highest during migration (10%) and declined to 6% in tropically wintering female sandpipers. Premigratory birds increased body fat, but not pectoralis H-FABP, indicating that endurance flight training may be required to stimulate H-FABP expression. Juveniles making their first migration had lower pectoralis H-FABP than adults, further supporting a role for flight training. Aerobic capacity, measured by citrate synthase activity, and fatty acid oxidation capacity, measured by 3-hydroxyacylCoA-dehydrogenase and carnitine palmitoyl transferase activities, did not change during premigration but increased during migration by 6, 12, and 13%, respectively. The greater relative induction of H-FABP (ϩ70%) with migration than of catabolic enzymes suggests that elevated H-FABP is related to the enhancement of uptake of fatty acids from the circulation. Citrate synthase, 3-hydroxyacyl-CoA-dehydrogenase, and carnitine palmitoyl transferase were positively correlated within individuals, suggesting coexpression, but enzyme activities were unrelated to H-FABP levels. endurance exercise; fuel selection; lipid transport; metabolism THE INSTANTANEOUS COST OF flight is high relative to other forms of locomotion; flying birds expend energy at 10 to 15 times basal metabolic rate (BMR), and the minimum cost of flight may be twice the aerobic limit (V O 2 max ) of similarly sized running mammals (4, 38). In the special case of migratory flight, during which this intensity of exercise is maintained for as long as 50 or even 100 h, energy metabolism is almost completely dominated (85-95%) by the oxidation of exogenous fatty acids (FA) delivered to flight muscles from extramuscular adipose tissue (21,23,44). The use of stored fat as a metabolic fuel makes migratory flight possible, yet there currently exists no general mechanistic understanding of how birds achieve the high rates of exogenous FA transport and oxidation required to support such high-intensity endurance exercise.The most complete information on fuel selection during exercise comes from studies of running mammals (including humans). Generally, the relative contribution of FA oxidation to total fuel demand declines as exercise intensity increases, with the balance of energy derived mainly from carbohydrate oxidation (36). Exogenous FA contribute only a small fraction of the energy needed for exercise of even moderate intensity, and near V O 2 max exogenous FA oxidation contributes ϳ10% of energy demand (43, 45). The rate of utilization of exogenous FA appears to be most limited by transport across the sa...

Harvard University Press, 1987.) £23.95. appearance of an insect and the heart beating once more stimulated discussions of the meaning of life and whether Polypedilum should be the first interstellar traveller as its ancestors perhaps once were.Had we had this book it would have been a reminder that metabolic arrest is a continuum and that many organisms have been able to harness the necessary mechanisms to some extent or other. D. F. HOULIHAN Scientific Basis of Dermatology. A Physiological Approach. Edited by A. J. THODAY and P. S. FRIEDMANN. Pp 375. (Churchill Livingstone, 1986.) £40.00.An understanding of the processes occurring in diseased skin relies heavily on a prior knowledge of skin physiology. This book sets out, in one volume, to discuss normal skin function and to use this as a background for a consideration of selected types of skin disease.This book is divided into two sections of approximately equal length. The first section deals with normal cutaneous physiology. An introductory chapter, which provides a foundation in the form of an overview, is followed by eight others which discuss mechanical and physical functions, resistance to permeability, protection against ultraviolet radiation and the skin's immune, sensory, thermoregulatory, communicatory and endocrine roles. The authors are, in the main, concerned with human skin physiology but refer in a number of areas, notably with respect to thermoregulation and the communicatory role of skin, to other species. This sortie into comparative dermatology not only aids an understanding of skin function in man but also extends the potential readership of the book,

Hummingbirds in flight display the highest rates of aerobic metabolism known among vertebrates. Their flight muscles possess sufficient maximal activities of hexokinase and carnitine palmitoyltransferase to allow the exclusive use of either glucose or long-chain fatty acids as metabolic fuels during flight. Respiratory quotients (RQ = VCO2/VO2) indicate that fatty acid oxidation serves as the primary energy source in fasted resting birds, while subsequent foraging occurs with a rapid shift towards the use of carbohydrate as the metabolic fuel. We suggest that hummingbirds building up fat deposits in preparation for migration behave as carbohydrate maximizers (or fat minimizers) with respect to the metabolic fuels selected to power foraging flight.