Digital transcriptome analysis indicates adaptive mechanisms in the heart of a hibernating mammal

Brauch, Katharine M.; Dhruv, Nirish; Hanse, Eric A.; Andrews, Matthew T.

doi:10.1152/physiolgenomics.00076.2005

Cited by 78 publications

(62 citation statements)

References 38 publications

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“…Low heart rates and cardiac output generally lead to chamber dilation due to volume overload (Verduyn et al, 2001;Schoenmakers et al, 2003). These conditions in hibernators may have led to a noted variety of cardiac adaptations (Folk et al, 1970;Caprette and Senturia, 1984;Milsom et al, 1993;Milsom et al, 1999;Burlington and Darvish, 1998;Brauch et al, 2005). In humans, cardiovascular function ceases with a cessation of pacemaker conduction at about 20°C, and this acute failure masks more chronic failure of the heart where pumping function can be maintained at a lower temperature in rats and mice.…”

Section: Discussionmentioning

confidence: 99%

“…Individuals transition from an active, euthermic state (37°C) to a hibernating state where torpid body temperature falls to 3-5°C but is punctuated repeatedly by arousals to euthermy. During bouts of torpor over a 6 month hibernation, these animals may be completely inactive for 2 weeks at a time at near-freezing temperatures, while arousals may last 24 h. Cardiovascular adaptations must occur for the myocardium to remain healthy and efficient during a period of extremely low temperatures, and low heart rate and cardiac output (Folk et al, 1970;Caprette and Senturia, 1984;Milsom et al, 1993;Milsom et al, 1999;Burlington and Darvish, 1998;Brauch et al, 2005). Non-hibernators that suffer from low heart rate conditions alone will develop cardiac chamber remodeling and congestive heart failure over time (Kertesz et al, 1997;Verduyn et al, 2001;Schoenmakers et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

Nelson

Rourke

2013

Journal of Experimental Biology

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SUMMARYDeep hibernators such as golden-mantled ground squirrels (Callospermophilus lateralis) have multiple challenges to cardiac function during low temperature torpor and subsequent arousals. As heart rates fall from over 300 beats min -1 to less than 10, chamber dilation and reduced cardiac output could lead to congestive myopathy. We performed echocardiography on a cohort of individuals prior to and after several months of hibernation. The left ventricular chamber exhibited eccentric and concentric hypertrophy during hibernation and thus calculated ventricular mass was ~30% greater. Ventricular ejection fraction was mildly reduced during hibernation but stroke volumes were greater due to the eccentric hypertrophy and dramatically increased diastolic filling volumes. Globally, the systolic phase in hibernation was ~9.5 times longer, and the diastolic phase was 28× longer. Left atrial ejection generally was not observed during hibernation. Atrial ejection returned weakly during early arousal. Strain echocardiography assessed the velocity and total movement distance of contraction and relaxation for regional ventricular segments in active and early arousal states. Myocardial systolic strain during early arousal was significantly greater than the active state, indicating greater total contractile movement. This mirrored the increased ventricular ejection fraction noted with early arousal. However, strain rates were slower during early arousal than during the active period, particularly systolic strain, which was 33% of active, compared with the rate of diastolic strain, which was 67% of active. As heart rate rose during the arousal period, myocardial velocities and strain rates also increased; this was matched closely by cardiac output. Curiously, though heart rates were only 26% of active heart rates during early arousal, the cardiac output was nearly 40% of the active state, suggesting an efficient pumping system. We further analyzed proportions of cardiac myosin heavy-chain (MyHC) isoforms in a separate cohort of squirrels over 5 months, including time points before hibernation, during hibernation and just prior to emergence. Hibernating individuals were maintained in both a 4°C cold room and a 20°C warm room. Measured by SDS-PAGE, relative percentages of cardiac MyHC alpha were increased during hibernation, at both hibernacula temperatures. A potential increase in contractile speed, and power, from more abundant MyHC alpha may aid force generation at low temperature and at low heart rates. Unlike many models of cardiomyopathies where the alpha isoform is replaced by the beta isoform in order to reduce oxygen consumption, ground squirrels demonstrate a potential cardioprotective mechanism to maintain cardiac output during torpor. Received 25 March 2013; Accepted 4 September 2013Key words: hibernation, MyHC, echocardiogram, atrial contraction, cardiac function. Echocardiogram and myosin of hibernatorsThe myosin heavy-chain isoforms (MyHC) are crucial determinants of contractile performance in cardiac muscle t...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

Nelson

Rourke

2013

Journal of Experimental Biology

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“…Enhanced mTORC1 phosphorylation during the entry stage could support an increase in the synthesis of selected proteins that are crucial to long-term survival in torpor. Indeed, previous studies on ground squirrel have identified a number of proteins that are selectively upregulated during torpor including, glucose-regulated protein 78, peroxisome proliferator-activated receptors- (PPAR-), PPAR- coactivator 1-, and peroxiredoxins (Prdx 1, 2 and 3) as well as enhanced expression of a variety genes, among them NADH-ubiquinone oxidoreductase subunit 2, myosin light chain 1 ventricular isoform, fatty acid binding proteins, adipophilin, mitochondrial uncoupling protein 2, pyruvate dehydrogenase kinase 4 and RNA binding motif protein 3 (Fahlman et al, 2000;Hittel and Storey, 2001;Storey and Storey, 2004;Eddy et al, 2005;Brauch et al, 2005;Mamady and Storey, 2006;Morin and Storey, 2008;Yan et al, 2007). These proteins are responsible for making crucial alterations that aid torpor survival, such as enhancing capacity for fatty acid metabolism and contributing to long-term cell preservation by elevating protein chaperones and antioxidant defenses.…”

Section: Thr1462mentioning

confidence: 99%

Regulation of the mTOR signaling network in hibernating thirteen-lined ground squirrels

Storey

2012

Journal of Experimental Biology

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SUMMARYFor many small mammals, survival over the winter months is a serious challenge because of low environmental temperatures and limited food availability. The solution for many species, such as thirteen-lined ground squirrels (Ictidomys tridecemlineatus), is hibernation, an altered physiological state characterized by seasonal heterothermy and entry into long periods of torpor that are interspersed with short arousals back to euthermia. During torpor, metabolic rate is strongly reduced to achieve major energy savings, and a coordinated depression of non-essential ATP-expensive functions such as protein synthesis takes place. This study examines the mammalian target of rapamycin (mTOR) signaling pathway, a crucial component of the insulin receptor network, over six stages of the torpor-arousal cycle of hibernation. Immunoblots showed that the phosphorylation state of mTOR Ser2448 was strongly reduced in skeletal muscle (by 55%) during late torpor but increased by 200% during early arousal compared with euthermia. However, the phosphorylation state of this residue remained relatively constant in cardiac muscle during torpor but was enhanced during entrance into torpor and early arousal from torpor stages (by 2.9-and 3.2-fold, respectively). Phosphorylation states of upstream regulators of mTOR, p-Akt Thr473 and p-TSC2 Thr1462, were also suppressed in skeletal muscle by 55 and 51%, respectively, during late torpor, as were selected downstream substrates -p-4E-BP1Thr46 and p-S6 Ser235 contents dropped by 74 and 41%, respectively. Overall, the results indicate suppressed mTOR signaling in skeletal muscle, but not cardiac muscle, during torpor. By contrast, activation of mTOR and other components of the mTORC1 complex (p-PRAS40 Thr246 and GL) occurred during early arousal in both skeletal and cardiac muscle.

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“…In contrast to single-gene expression analysis, the genome-wide approach also allows for identification of coordinated transcriptional changes in functional groups of regulatory genes within metabolic and signaling pathways. Recent studies of differential gene expression at the genomic scale on several species of hibernating small mammals have detected expression changes for hundreds of genes when comparing animals sampled in different stages during hibernation and nonhibernating periods (5,42,43,44). Coordinated transcriptional changes associated with hibernation have identified groups of co-regulated genes involved in carbohydrate, fatty acid and protein metabolism, detoxification, and molecular transport.…”

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confidence: 99%

Elevated expression of protein biosynthesis genes in liver and muscle of hibernating black bears (Ursus americanus)

Fedorov

Goropashnaya

Tøien

et al. 2009

Physiological Genomics

125

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We conducted a large-scale gene expression screen using the 3,200 cDNA probe microarray developed specifically for Ursus americanus to detect expression differences in liver and skeletal muscle that occur during winter hibernation compared with animals sampled during summer. The expression of 12 genes, including RNA binding protein motif 3 (Rbm3), that are mostly involved in protein biosynthesis, was induced during hibernation in both liver and muscle. The Gene Ontology and Gene Set Enrichment analysis consistently showed a highly significant enrichment of the protein biosynthesis category by overexpressed genes in both liver and skeletal muscle during hibernation. Coordinated induction in transcriptional level of genes involved in protein biosynthesis is a distinctive feature of the transcriptome in hibernating black bears. This finding implies induction of translation and suggests an adaptive mechanism that contributes to a unique ability to reduce muscle atrophy over prolonged periods of immobility during hibernation. Comparing expression profiles in bears to small mammalian hibernators shows a general trend during hibernation of transcriptional changes that include induction of genes involved in lipid metabolism and carbohydrate synthesis as well as depression of genes involved in the urea cycle and detoxification function in liver. gene expression; hibernation; translation; RNA binding protein motif 3 MAMMALIAN HIBERNATION IS a physiological and behavioral adaptation involving a coordinated suppression of heat production and body temperature wherein whole body metabolism and energy demand are significantly reduced over several days to several months. During hibernation, heart and respiration rates, blood flow, and oxygen consumption decrease dramatically to Ͻ10% of normal or basal rates (2, 4). These physiological changes do not represent a loss of homeostasis but instead are precisely controlled and spontaneously reversible, and they allow individual animals to survive highly seasonal or unpredictable environments where food availability becomes lacking (7, 12). The molecular and genetic basis of hibernation in small mammals has only recently begun to be described, and little is known about its evolutionary history. Hibernating species have been found in diverse families among seven orders of mammals (26), however, and the interspersed phylogenetic distribution of hibernating and nonhibernating species has led to the hypothesis that rather than requiring the creation of novel gene products, hibernation results from the differential expression of genes that exist widely among mammals (35).Microarray technology provides powerful means for the unbiased detection of differences in expression of thousands of genes in a single hybridization experiment (14). In contrast to single-gene expression analysis, the genome-wide approach also allows for identification of coordinated transcriptional changes in functional groups of regulatory genes within metabolic and signaling pathways. Recent studies of differential gen...

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Digital transcriptome analysis indicates adaptive mechanisms in the heart of a hibernating mammal

Abstract: . Digital transcriptome analysis indicates adaptive mechanisms in the heart of a hibernating mammal.

Cited by 78 publications

References 38 publications

Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

Regulation of the mTOR signaling network in hibernating thirteen-lined ground squirrels

Elevated expression of protein biosynthesis genes in liver and muscle of hibernating black bears (Ursus americanus)

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