Hibernating Bears (Ursidae)

Metabolic Magicians of Definite Interest for the Nephrologist

Peter Stenvinkel; Alkesh H Jani; Richard J Johnson

Disclosures

Kidney Int. 2013;83(2):207-212. 

In This Article

Unparalleled Ability to Preserve Muscle Mass During Hibernation

Skeletal muscle atrophy (sarcopenia) occurs in human muscles with inactivity, especially in the elderly. Treatment of sarcopenia in chronic debilitating conditions is notoriously difficult, as studies suggest that it may require either stimulating mitochondrial growth or blocking of the ubiquitin-dependent proteolytic system,[29] for which effective therapies are not yet available. It is noteworthy that bears appear to be protected from developing sarcopenia, as they lose only about 10–15% of their muscle protein content and overall force-generating capacity during hibernation.[30] Tinker et al.[31] documented the extent of protein loss and alteration of muscle-fiber characteristics in black bears during hibernation and found that muscle-fiber number and cross-sectional area were unchanged, suggesting only limited muscle atrophy. In another study, Hershey et al.[32] collected muscle samples during the summer and winter in captive brown bears and measured protein concentration, fiber-type composition, fiber cross-sectional area, and twitch characteristics. As minimal skeletal muscle atrophy occured between seasons, bears have developed a unique physiological strategy to maintain muscle tonus during months of inactivity.

The most important reason why bears have achieved this magical trick is probably the synthesis of new amino acids from urea nitrogen that help preserve lean body mass.[19,33] However, other mechanisms may also be operative. It has been hypothesized that isometric muscle contractions in response to shivering during the winter may help retain muscle strength by rhythmic stimulation.[33] Others have reported that during hibernation the bear develops hypothalamic hypothyroidism[34] and increased testosterone production.[35] These hormonal adaptations create a balance of anabolism and catabolism that prevents muscle wasting during the hibernating period in which both starvation and immobilization occur. As activators of sirtuins, such as resveratrol, were recently shown to ameliorate metabolic disorders and muscle wasting in diabetic rats,[36] the hypothesis that sirtuins are expressed in bears before hibernation could also be considered. Additional proposed mechanisms include alterations in the growth hormone and insulin-like growth factor axis[37] and inhibition of skeletal muscle catabolism by blocking the renal–CNS–skeletal muscle sympathetic nerve axis.[38]

Two novel observations have helped to further elucidate this fascinating metabolic adaption in bears. Fuster et al.[39] demonstrated that hibernating bears produce a powerful proteolytic inhibitor that blocks muscle wasting associated with immobilization. If this factor could be identified, it could serve as a treatment strategy for conditions in which protein energy wasting is a common feature. Second, Tøien et al.[6] unexpectedly demonstrated that metabolic depression is achieved primarily via metabolic inhibition, whereas the decrease in body temperature has only a minor role. Thus, it could be speculated that in bears hibernation requires increased expression of hibernation-specific genes to maintain cell function, such as gluconeogenesis, cytoprotection, and lipid metabolism, and downregulation of processes of energy production and consumption while maintaining cellular homeostasis.[40,41]

The molecular and genetic basis of hibernation physiology in mammals has recently been studied using large-scale genomic approaches. Fedorov et al.[42] found that hibernating American black bears demonstrate a balanced proportion of upregulated and downregulated genes that are differentially expressed in the liver. During hibernation, there is an induction of genes involved in fatty acid β-oxidation and carbohydrate synthesis and depression of genes involved in lipid biosynthesis, carbohydrate catabolism, cellular respiration, and detoxification pathways. A recent study of Japanese black bears (Ursus thibetanus japonicus) showed that the modulation of gene expression is not static but changes throughout the hibernation period.[43] The stimuli for the induction and depression of key gene expression during hibernation are not known. It would be of much interest to link phenotypic plasticity in hibernating bears and changes in the gene-specific epigenome.[22] In plants, remarkable effects of seasons on the epigenome have been demonstrated.[44,45]

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