Chapter 4 - Metabolic rate depression: The biochemistry of mammalian hibernation
Section snippets
Abstract
During winter hibernation, small mammals fall into long periods of deep cold torpor where metabolic rate is suppressed by > 90% and core body temperature can fall to near 0 °C. Studies with hibernators illustrate the molecular regulatory mechanisms that coordinate the suppression of metabolic functions during torpor, reprioritize energy use, and preserve/stabilize macromolecules to support long-term viability during cold torpor. This review explores mechanisms including posttranslational
Introduction: Hypometabolism, Hibernation, and Man
Life on earth flourishes whenever environmental conditions are permissive but organisms must also endure challenges that are incompatible with normal life, for example, lack of food, extremes of heat or cold, low oxygen, desiccation, etc. In some cases, such stresses are unpredictable in duration/degree and in others they are circadian or circannual challenges. For many organisms, survival under stress is ensured by coordinating a strong suppression of metabolic functions and entering a
Hibernation and Clinical Science
Applied methods that could impose regulated metabolic suppression in humans would have a number of potential biomedical applications to clinical science [6], [24]. These could be used to improve the “shelf life” of tissues/organs removed for transplantation. Present methods for organ explants rely almost exclusively on cold ischemia (i.e., packing in ice) but both cold and ischemia cause severe metabolic damage to the organs of nonhibernating mammals that make them nonviable in a matter of
The Basics of Hibernation
The field of mammalian hibernation is huge and covers many aspects of ecology, physiology, biochemistry, and molecular biology. The present chapter will focus mainly on metabolic regulation and gene expression as it applies to hypometabolism in hibernators. Before beginning, however, a brief orientation to the phenomenon is needed. Mammalian hibernation is as a period of seasonal heterothermy that is characterized by cycles of torpor and arousal and follows a circannual clock. Some hibernators
Regulation of Enzymes and Functional Proteins
In all animal systems that have been studied, the transition into a hypometabolic state involves both (a) global suppression of all metabolic functions to achieve major energy savings, and (b) reprioritization of energy use to sustain vital activities (e.g., maintenance of membrane potential difference) while virtually halting many optional activities (e.g., biosynthesis, cell cycle, growth, etc.) [1], [2], [3]. Enzymes and other types of functional proteins (such as transporters, ribosomal
Reversible Protein Phosphorylation
The addition or removal of covalently bound phosphate groups to proteins via the action of protein kinases or protein phosphatases is the most powerful and widespread mechanism of metabolic control in cells and our research has shown that it is a major regulatory mechanism in all forms of hypometabolism including daily torpor and seasonal hibernation [1], [2], [3], [41]. Reversible protein phosphorylation (RPP) often provides on/off control of enzymes, can make large-scale changes to
Global Mechanisms of Transcription and Translation Control
A high percentage of the energy budget of most cells is spent on gene transcription and protein translation. Hence, entry into all forms of hypometabolism involves global suppression of transcription and translation [2], [5]. For example, the rate of [3H]-uridine incorporation into RNA was just 6–26% of the euthermic value in different organs of hibernating hamsters [51] and 34% and 15% of the euthermic value in ground squirrel brain and kidney when quantified at a constant temperature [62],
Gene Discovery
In recent years, the availability of gene and protein screening techniques has allowed major advances to be made in our understanding of the gene/protein expression changes that contribute to hibernation. Multiple approaches have been taken including cDNA library screening [81], [82], subtractive hybridization [57], [83], cDNA array screening using both heterologous [44], [84], [85], [86] and homologous [87] arrays as well as Illumina bead array technology [88]. Other studies have taken a
Metabolic Signaling in Hibernation—Protein Kinases and Phosphatases
Intracellular signal transduction cascades are at the heart of torpor regulation triggering both global and differential controls on enzymes and functional proteins and, through their regulation of Tfs, mediating changes in gene expression. Studies to date have explored the involvement of selected protein kinases and protein phosphatases in the regulation of torpor. For example, cyclic AMP-activated protein kinase dependent protein kinase cyclic 3',5'-adenosine monophosphate dependent protein
Transcription Factors and Coordinated Gene Expression
We have recently begun to take a new approach to understanding the gene/protein regulation that supports the hibernating phenotype. This is to identify the Tfs that are activated when animals enter torpor. Because each Tf typically regulates a known group of genes that are dedicated to addressing a particular cell function, and because the activation status of many Tfs can now be readily assessed (either with selective immunoblotting methods for individual Tfs or with commercial screening
Conclusions and Future Directions
From our studies of mammalian hibernation and other forms of animal hypometabolism, we have assembled a list of principles and mechanisms that are important to regulating entry into and arousal from torpor as well as sustaining viability during long-term dormancy. These include posttranslational mechanisms for turning down/off the activities of enzymes and functional proteins, differential regulatory controls applied to selected enzymes, mechanisms to store mRNA transcripts and to stabilize
Acknowledgments
We thank the many graduate students from our lab who have worked hard to elucidate the biochemical adaptations that support mammalian hibernation. Research in the Storey lab is supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada and the Canada Research Chairs program.
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2022, Developmental BiologyStable suppression of skeletal muscle fructose-1,6-bisphosphatase during ground squirrel hibernation: Potential implications of reversible acetylation as a regulatory mechanism
2021, CryobiologyCitation Excerpt :These state-dependent needs for carbohydrates suggests some form of rapid regulation between active and torpid states. This has been well established for glycolysis [30,34] but is relatively unknown for glucon eogenesis. While skeletal muscle is not typically thought of as a gluconeogenic center, substantial evidence exists that gluconeogenic enzymes are prevalent in muscle and that a substantial portion of muscle-derived lactate can be converted into intramuscular glycogen [9,24].