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MAMMALS ON ICE : MAMMALS ON ICE : HIBERNATIONHIBERNATION
www.carleton.ca/~kbstoreywww.carleton.ca/~kbstorey
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Myotis lucifugus, little brown bat
Spermophilus tridecemlineatus,13-lined ground squirrel
Spermophilus richardsonii,Richardson’s ground squirrel
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• Seasonal phenomenon
• Pre-hibernation hyperphagia
• Gain up to 40% of body mass
• Need polyunsaturated fats
• Find hibernaculum: dark, near 0°C
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• drop in body temperature• reduced heart rate• apnoic breathing• some muscle atrophy • periods of torpor lasting weeks• non-REM sleep• oleamide increases in brain
• suppression of carbohydrate oxidation
• RQ of 0.7 = lipid oxidation
Stewart JM, Boudreau NM, Blakely JA &Storey KB. 2002. J. Thermal Biol. 27, 309-315.
Oleamide in groundsquirrel brain
(ng/g)
Euthermic Hibernating0
200
400
600
800
Month
Body temperature
MR falls to fraction of normal
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• Metabolism inhibited causing Tb to fall
• Metabolic rate falls to <5% of normal
• Smaller animals cool down faster
• Q10 values up to 15
• Reversible in arousal
• Torpor bout duration 4 days to 2 weeks
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Estivation
METABOLIC RATE METABOLIC RATE DEPRESSIONDEPRESSION
Diapause
Freezing
Anoxia
Hibernation
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GENESGENES
Transcription
RNAsRNAs
Control byControl bytranscriptional regulationtranscriptional regulation
Control byControl bytranslational regulationtranslational regulationTranslation
PROTEINSPROTEINS(ENZYMES)(ENZYMES)
Control byControl byproteasesproteases INACTIVEINACTIVE
ENZYMEENZYME
NoModification
FUNCTIONALFUNCTIONALENZYMESENZYMES
Covalentmodification
Degradation
Control by post-Control by post-translationaltranslationalmodificationmodification
ACTIVEACTIVEENZYMESENZYMES
Inhibitionand
Activation
Control at level ofControl at level ofenzyme functionenzyme function
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METABOLISM IN METABOLISM IN HIBERNATIONHIBERNATION
• mRNA synthesis • Protein synthesis • Ion Pumping • Fuel use (esp. CHO)• O2 consumed
ATP turnover to <5% of normal
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PRINCIPLES OF PRINCIPLES OF HIBERNATIONHIBERNATION
1. Metabolic rate reduction
2. Control by protein kinases(SAPKs, 2nd messenger PKs)
3. Selective gene activation
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Nucleus
GENESON/OFF
mRNAs
[ i + e Factors]
PROTEINS
Ca+2
KINASES (2nd)
PATHWAYS
SMW
CHO
AA
ATP
?SAPK
ATP
ADP
MITOGENES
FAT
[Trans.F] Na
K
ETC
P PROT
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Nucleus
GENESON/OFF
mRNAs
[ i + e Factors]
PROTEINS
Ca+2
KINASES (2nd)
PATHWAYS
SMW
CHO
AA
ATP
?SAPK
ATP
ADP
MITOGENES
FAT
[Trans.F] Na
K
ETC
P PROT
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HIBERNATION INDUCED HIBERNATION INDUCED CHANGESCHANGES
• Protein Synthesis slows to 1% • Pumps & Channels closed • Energy Production slows to 5% • Energy Utilization slows to 2%• Few ‘SAP’ kinases activated
• Gene ‘inactivation’ ( mRNA )• Few Genes activated (1-2%)
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PROTEIN KINASESPROTEIN KINASES
PROTEIN
nATP nADP
PROTEIN-(P)n
• Covalent modification by phosphorylation
• Families of protein kinases: PKA (cAMP), PKG (cGMP), CaM (Ca2+), PKC (Ca2+, PL,DG)
• SAPKs : daisy chain phosphorylations
• Regulation via interconversion of active vs subactive forms of protein substrates
• p38, ERK (1/2), JNK, AMPK, AKT (mTOR)
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PP
PP PP
PP
PiPiProtein
Phosphatase
ATPATP ADPADPProtein Kinase
P & deP enzymesseparate on ion
exchange columns
ReversibleReversiblephosphorylationphosphorylation
control of enzymescontrol of enzymes
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PATHWAY CONTROL IN PATHWAY CONTROL IN HIBERNATIONHIBERNATION
• Glycolysis (GP, GS, PFK, PK)• Fat synthesis (ATP-CL, ACC)• CHO fuel use (PDH)• Translation (eIF2α, eEF2)• Ion pumps (NaK, Ca-ATPase)
• the usual suspects, TextBook
Phospho / de-Phospho
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1. Novel PhosphoEnzymes: BioInformatics + Phospho-analyses 2. 32P-ATP labeling studies3. Purification / Properties 4. Structure / Function5. Phospho-sites
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Post-translational Modifications:Post-translational Modifications: The Next Generation The Next Generation
Novel Phosphorylation ControlCK, GDH, Hexokinase, G6PDH,
LDH, NADP-IDH, α-GPDH, AMPD, GAPDH, FBPase, Antioxidant
enzymes
PTM: Acetylation, Methylation, SUMOylation
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HIBERNATION INDUCED HIBERNATION INDUCED CHANGESCHANGES
• Protein Synthesis slows to 1% • Pumps & channels closed • Energy Production slows to 5% • Energy Utilization slows to 2%• Few ‘SAP’ kinases activated
• Gene ‘inactivation’ ( mRNA )• Few Genes activated (1-2%)
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TURNING OFF GENES:TURNING OFF GENES:Role of EpigeneticsRole of Epigenetics
Epigenetics:Epigenetics: - Stable changes in gene activity that do not involve changes in DNA sequence
Common mechanisms:Common mechanisms: - DNA methylation - Histone modification / histone variants e.g. acetylation, phosphorylation - Regulatory non-coding RNAs
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Transcription Transcription Suppression in Hibernator Suppression in Hibernator
MuscleMuscle
• Phospho-Histone H3 (Ser10) levels reduced
• Acetyl-Histone H3 (Lys23) levels reduced * Both inhibit Transcription ** Both inhibit Transcription *
• Histone Deacetylase activity increased 80%
• HDAC 1 & 4 protein levels increased
• RNA Polymerase II activity Decreased
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Regulatory non-coding RNAs Regulatory non-coding RNAs
• Small RNAs ~22 nucleotides in length
• Highly conserved across species
• Bind to 3’ UTR of mRNAs
• Could be 1000, affect 60 % of genes
• Disease involvement
• Act to :
- Block translation of mRNA - Target mRNA for degradation
microRNAmicroRNA
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Cuellar TL, McManus MT. J Endocrinol. 187(3):327-332, 2005.
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Are miRNAs differentially regulated Are miRNAs differentially regulated in hibernators?in hibernators?
• Yes! Selected miRNAs were regulated in heart, muscle & kidney of hibernating 13-lined ground squirrels
(Morin, Dubuc & Storey, 2008, Biochim Biophys Acta 1779:628-633)
miRNA Fold change Process in higher vertebrates
Mir-1 2.0 Myogenesis
Mir-133a 2.4 Myogenesis
Mir-206 2.6 Myogenesis
Let-7 2.0 Cell cycle
Mir-26 2.4 Hypoxia
Mir-451 2.6 Erythropoiesis
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Turning it all Turning it all offoff
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Estivation
METABOLIC RATE METABOLIC RATE DEPRESSIONDEPRESSION
Diapause
Freezing
Anoxia
Hibernation
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HIBERNATION INDUCED HIBERNATION INDUCED CHANGESCHANGES
• Protein Synthesis slows to 1% • Pumps & channels closed • Energy Production slows to 5% • Energy Utilization slows to 2%• Few ‘SAP’ kinases activated
• Gene ‘inactivation’ ( mRNA )• Few Genes activated (1-2%)
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ROLE OF ROLE OF TRANSCRIPTIONTRANSCRIPTION
• Global rate of mRNA synthesis depressed. Method: nuclear run-on
• Are selected genes up-regulated ?
• TO ASSESS GENE UPREGULATION:TO ASSESS GENE UPREGULATION:
What new mRNAs are created - cDNA library, Gene Chip
Sequenced genome(s) as of 2011 Sequenced genome(s) as of 2011
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cDNA ARRAY SCREENINGcDNA ARRAY SCREENING
Euthermic Hibernating
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cDNA ArrayscDNA Arrays- Methods- Methods- MaterialsMaterials- SourcesSources- Publications- Publications
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GENE CHANGES IN GENE CHANGES IN HIBERNATIONHIBERNATION
• cDNA Library screen - Mitochondrial Genes - AOE - FABP, CPT, etc. - Shock proteins (GRP, HSP) - Transcription factors • DNA Chip ~1-2%
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CONTROL REGION OF A CONTROL REGION OF A TYPICAL EUKARYOTIC GENETYPICAL EUKARYOTIC GENE
Epigenetics = OFF) : Epigenetics = OFF) : • microRNAmicroRNA
• phospho-RNA Polymerasephospho-RNA Polymerase• Histones modified Histones modified
• HDAC / HAT changesHDAC / HAT changes
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TRANSCRIPTION FACTORS TRANSCRIPTION FACTORS
• ATF (Glucose Regulated Proteins)
• HIF (O2), HSF (Hsp)
• NFkB (IkB-P), Nrf-2 (**), NRF-1
• PPAR, PGC, RXR, chREBP, CREB-P
• STAT, SMAD, p53-P, HNF, AP (1,2)
• Methods: EMSA, CHiP
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Nrf2/ARE pathwayNrf2/ARE pathway
Antioxidant proteins(e.g. GSTs, HO1)
ARE
Nucleus
Cytoplasm
Small Maf
Nrf2
Keap1
Actin
Reactive Oxygen Species (ROS)
Activation
Dissociation
Nrf2 P
Nrf2 P
Small Maf Nrf2 P
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Nrf-2Nrf-2• Increased Nrf-2 protein & P
• Increased Nrf-2 in the Nucleus
• Increased levels of co-Tf: MafG
• Downstream gene activation:
• GST, HO-1, HO-2, Peroxiredoxin
• Thioredoxin, SOD (Cu/Zn & Mn)
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Nrf2/ARE pathwayNrf2/ARE pathway
Antioxidant proteins(e.g. GSTs, HO1)
ARE
Nucleus
Cytoplasm
Small Maf
Nrf2
Keap1
Actin
Reactive Oxygen Species (ROS)
Activation
Dissociation
Nrf2 P
Nrf2 P
Small Maf Nrf2 P
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Protein Regulation of Nrf2Protein Regulation of Nrf2
100 kDa
57 kDa
E H
Nrf2
Actin
Nrf2
Euthermicvs
Hibernating
Squirrel Nrf2 57kDa and 100kDa protein expression(hibernating vs.euthermic)
00.5
11.5
22.5
33.5
44.5
B.A.T. Brain Heart Kidney Liver Lung Muscle W.A.T.rati
o:
hib
ern
ati
ng
vs
. eu
the
rmic
57KDa
100KDa
* *
* *
* *
**
*
RatioHib:Euth
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Nrf2 distribution between nuclearNrf2 distribution between nuclearand cytoplasmic fractionsand cytoplasmic fractions
E H E H Nucleus Cytoplasm
57 kDa
100 kDa
Nucleus CytoplasmE H E H
57 kDa
100 kDa
Moved to nucleus
Nrf2 (57 KDa and 100 KDa) Protein Expression inMuscle Nuclear and Cytoplasmic Fractions
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Muscle Nuclear Fraction Muscle Cytoplasmic Fraction
Hib
ern
atin
g v
s. E
uth
erm
ic
57KDa
100KDa
**
*
Muscle
Hib
: E
uth
Nrf2 (57 KDa and 100 KDa) Protein Expression in LiverNuclear and Cytoplasmic Fractions
00.20.40.60.8
11.21.41.6
Liver Nuclear Fraction Liver Cytoplasmic Fraction
Hib
ern
atin
g v
s. E
uth
erm
ic
57KDa
100KDa
*
*
Liver
Hib
: E
uth
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Nrf2 Timecourse in HeartNrf2 Timecourse in Heart
• Nrf2 protein in early and late hibernation
Up-regulation “cascade”.
Active incold room
(37°C)
Entrance
(T-drop)
Early Hibern.
(~5-7°C)
Late Hibern.
(~5-7°C)
Early Arousal(T-gain)
FullyAroused(37°C)
Nrf2
CuZnSOD
AFAR1
HO-1
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PeroxiredoxinsPeroxiredoxins
• Detoxify / reduce hydroperoxides
• Expressed at high levels
• ARE in promoter region of Prdx genes
•Nrf2 activated
0
2
4
6
8
10
12
14
16
18
Brown adipose tissue Heart
scan
ned
in
ten
sit
y o
f h
ibern
ati
ng
versu
s
eu
therm
ic
peroxiredoxin-1
peroxiredoxin-2
peroxiredoxin-3
BAT
Heart
Euth Hib
Prdx1 Prdx3Prdx2Peroxiredoxin protein levels
Euth HibEuth HibR
ati
o b
and inte
nsi
tyH
ib :
Euth
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Peroxiredoxin ActivityPeroxiredoxin Activity
• Protein level correlates with increased activity
• Assays in BAT and heart with thioredoxin, thioredoxin reductase and NADPH:
Kim et al., 2005
0
0.5
1
1.5
2
2.5
3
3.5
4
Brown adipose tisuue Heart
Rat
io o
f hib
erna
ting
vers
us e
uthe
rmic
act
ivity
Relative activity: Hibernating: euthermic
A
ctiv
ity
rati
o
Hib
: E
uth
BAT Heart
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Nrf ConclusionNrf Conclusion Activation of the Nrf2 pathway:Activation of the Nrf2 pathway:
Activated in early-late torpor, along with downstream gene protein products
Increased PRDX, HO & TRX protein and activity
Result:Result:
Detoxification of ROS, intracellular signaling control
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GENE CHIPS TRANSCRIPTION FACTORPROFILING
Data LeadsData Leads
ELISAs in plates
Confirm by EMSA
Confirm byRT-PCR,
Northern blots
TfDownstream genes
ROLE & CONTROL OF SYSTEM
Transgenics
Cell AssayRNAi Knock out Epigenetics
FUNCTIONAL ASSAYS
Protein levels - enzyme assay - antibodies : protein - functional analysis e.g. HIF EPO
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Where do we go from Where do we go from here?here?
• Applications of MRD research • Novel phosphorylations• Atrophy, hypertrophy -- autophagy for survival • Turning it all off -- microRNA• Epigenetics & adaptation • Life span extension• Antioxidant Defense• Cell cycle suppression• Unity through evolution
NEW DIRECTIONSNEW DIRECTIONS
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PRIMATE HIBERNATION!!GREY MOUSE LEMUR
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Hibernation and medicineHibernation and medicine
Primates !!
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Novel phosphorylations Novel phosphorylations
PP
PP PP
PP
PiPiProtein
Phosphatase
ATPATP ADPADPProtein Kinase
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Atrophy – HypertrophyAtrophy – Hypertrophy
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Turning it all Turning it all offoff
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Epigenetics in AdaptationEpigenetics in Adaptation
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Life span Life span extensionextension
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Unavoidable metabolic costs Unavoidable metabolic costs
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Unity through Evolution Unity through Evolution
WWCeDWWCeD
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HIBERNATIONHIBERNATION• J. STOREY• S. EDDY• D. HITTEL• J. MacDONALD• A. FAHLMAN• P. MORIN• C. HOLDEN• H. MEHRANI• J. NI
• M. HAPSATOU• S. TESSIER• M. WU• S. BROOKS• C. FRANK• J. HALLENBECK• D. THOMAS• A. RUBTSOV• J. STEWART
www.carleton.ca/~kbstoreywww.carleton.ca/~kbstorey
Funded by NSERC CanadaFunded by NSERC Canada