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65 Cards in this Set
- Front
- Back
Thyroid Hormone Regulation |
Hypothal ~> TRH ~> Ant Pit. ~> TSH ~> ThyG ~> T3/T4 |
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Tyrosine + Iodinated Derivatives |
Tyrosine + DIT + DIT = T4 Tyrosine + MIT + DIT = T3 Tyrosine + DIT + MIT = Reverse T3 |
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Deiodinase Enzymes |
D1/D2 = T4 ~> T3 (Expressed in Heart + Muscle) D3 = T3 ~> Reverse T3 |
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Main Effects of Thyroid Hormone |
1)Increased Oxygen Consumption (most tissues) i) more ATP Utilizing protein ii) more ATP Synthesizing proteins (from free ADP) iii) higher BMR 2)Growth/CNS Development i) dwarfis/cog impairments if LOW 3)Cardiovascular System i) Cardiac Hypertrophy from increased Beta -1-Adrenergic receptors |
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WILLIAM & HOLLOSZY MTC/MUSCLE & Thyroidtoxicosis |
Different muscle fiber types respond differently ST better than FT ~> higher [MTC] in ST |
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TERJUNG & KOENER Thyroidectomized Rats & Exercise |
(Norm Trained/Untrained & TZD Trained/Untrained) ~TDZ-sedentary rats had 1/2 as much [MTC] than Norm-Sedentary ~No Sig Diff between Norm-Trained / TDZ-Trained in [MTC] therefore T3 important for maintenance not exercise |
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IRRCHER #1 Timed Effects of T3 on AMPK/p38/PGC1a in -Soleus (S) // Plantaris (P) // Heart (H) |
p38 - S: doubled P: doubled first 2 hours then decreased H: increased over time AMPK - S: doubled up until 4 hours P: doubled first 2 hours then decreased H: Not Significant PGC1a - Not Significant in all 3 therefore T3 rapidly modifies Kinase activity in tissue specific fashion |
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IRRCHER #1 Possible Mechanisms of T3-Induced Gene Expression |
1) Direct binding of T3 on Thyroid Response Element 2) Non-Genomic binding of T3 on TF (p38/AMPK) 3) Genomic binding of TF containing T.RE in promotor |
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ROBINSON & HOOD T3 & Effects On mtDNA Diseases |
~COX activity increased for patients ~No significant difference in MTC mass b/w groups ~[ROS] increased in patients alongside higher [MnSOD] No effect on PGC1a |
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IRRCHER & ADHIHETTY PGC1a Protein levels with CCA/Denervation over time |
~50/60% increase >3days // stayed = ~5/7days ~> decrease on 10th day ~Rapid drop in protein levels + COX activity in 5days |
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BAAR HOLLOSZEY Acute Ex+Rest on PGC1a/NRF1-2 Protein Levels |
~ 2 fold increase in protein levels + binding of NRF1-2 on DNA |
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CALVO PRESENTATION PGC1a +/+ on Exercise Perf & MTC content |
+/+ mice had higher - FA oxidation + transport - Oxidative phosphorylation - CHO metabolism - Peak VO2 - Total VO2 ~> Work Ability -- Lower RER ~> Better FA Oxidation |
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SANDRI PGC1a +/+ & Denervation induced Atrophy |
~ Denervated WT atrophied while ~ (+/+) protected 2 fold against atrophy +/+ block FOXO-3 from binding to Atrogenes |
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Atrogenes |
Activate during disuse, FOXO-3 bind to Atrogin-1 stimulates protein degradation |
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WINDER AMPK Importance on PGC1a in FTR/FTW/STR |
Citrate Synthase measured in muscle fibres injected with 4weeks of AICAR FTW/FTR sig. increased but not STR ~> STR has high [MTC] |
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AMPK VS mTOR |
AMPK activated by ~ Increased Calcium from contractions ~ high AMP to low ATP ratio AMPK phosphorylates TSC2 which inhibits mTOR |
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IRRCHER #2 AICAR Regulation of MTC-BG |
Increase AICAR ~> Increase PGC1a levels w/ same increase in AMPK |
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IRRCHER #2 Human PGC1a Promoter Deletion Constructs Effect of AICAR on PGC1a |
(472-821) see increased response to AICAR Oglionucleotide made ~> Gel-Shift Assay ran on binding sites TF bound to EBOX/GATA when AICAR increased |
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IRRCHER #2 Effect of AICAR on PGC1a continued GATA/EBOX |
4 proteins bind to GATA/EBOX MyoD // Myogenin // USF1-2 // C-Myc AICAR ~> 1 of these to bind more to the EBOX Super Shift Gel Assay done with radioactive 32P label ~> USF-1 only protein to shift of the 4 Therefore AMPK ~> Phosph USF-1 to increase TF of PGC1a |
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MTC Morphology ~Protein Review |
Fusion Proteins ~Mfn-1 & 2 ~OPA1 Fission Proteins ~Fis1 ~Drp1 |
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French Paper MFN expression Post exercise |
Results fond increased mRNA expression post exercise @ 24H |
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MFN-2 in Obese rats/humans |
Both groups show sig. decrease in MFN-2 ~> decreased MFN-2 = decreased MTC-Network = decreased lipid metabolism With French paper taken into account ~> Exercise ameliorates adverse effects of obesity |
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SADIA IQBALL STUDY CCA // Denervation // Aging on Fis:Fus Proteins |
i) CCA: Fission proteins = N.S Fusion proteins = Significant ii) Denervation: Both Fis/Fus decrease favour Fis over Fus iii) Aging: Fis proteins increase, favour over Fus MTC Depth/Size: both increase with i) but decrease with ii) & iii) |
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SCHATZ Fundamentals of Protein Import into MTC |
1) Precursor contain pre-sequence ~> Matrix 2) ATP + Chaperones unfold + Begin interaction with TOM 3) -150mV difference in charge translocates protein 4) Complete translocation + cleaving of pre-sequence 5) Re-Folding by Intra-MTC chaperones ~> Targeting to part of cell |
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Measuring Pre-Cursor Protein In Vitro |
1) Plasmid Vector with i) Bacterial Promoter Region + Coding Sequence (MDH) 2) Add RNA-Polymerase for Transcription in vivo 3) Add Cell Extract for Translation in vivo ~Ribosomes, tRNA, 20 A.A. ~35S-Methionone Radioactive Tracer 4) Add MTC & Incubate 5) Separate proteins on gel base 6) Incubate gel w/ film for Radioactive bands 7) Pre-Cursor at top w/ imported father down |
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TAKAHASHI & HOOD Import into Matrix - SS VS IMF MTC |
Difference between SS & IMF ~IMF - higher protein import at all 5min intervals |
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TAKAHASHI - GORDON - JOSEPH CCA on MTC Protein Import |
Import Rate increases Protein Import Machinery increases CCA increases rate because machinery present increases
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SINGH & HOOD MTC Protein Import & Denervation |
Denervation causes ~Decreased State 3 Respiration ~Decreased PIM Expression ~Increased ROS production i) Apoptosis, Autophagy, Protein Degradation as result Leading to Decreased PIM Expression ~> Leading to lower [MTC] Leading to Muscle Atrophy |
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Protein Import in regard to Gene Expression |
Chronic exercisers have highest protein import rate because of higher PIM expression/Rate |
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YUAN ZHANG BAX/BAK in Protein Import |
(-/-) BAX/BAK reduces import into matrix increasing ROS ~> Inducing gene expression |
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YUAN ZHANG BAX/BAK Protein Import - Exercise Effects |
Exercise increases MTC-BG enough to raise COX activity in (-/-) BUT ~ (-/-) had lower endurance/work ability Exercise saved import rate + fixes problems with machinery |
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ADHIHETTY & HOOD MTC Mediated Apoptosis ~Caspase Dependent Pathway |
~BAX creates tetromer channel on OM allowing CytC escape ~ROS allows CytC unbinding from Cardiolipin i) CytC can escape through mtPTP ~CytC binds to apoptosome ~> Activate Caspase Casecade ~Casp-3 enters Nucleus = DNA Fragmentation HSP70 inhibits cascade from beginning |
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ADHIHETTY & HOOD MTC Mediated Apoptosis ~Caspase Independent Pathway |
~ROS regulates mtPTP ~> too high opens up ~Organelle swells with H20 releasing i) AIF & EndoG ~Enter nucleus = DNA Fragmentation HSP70 inhibits AIF/EndoG |
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BAINES Causes of mtPTP opening up |
1) Membrane Potential Dissipation 2) Reduced ATP-Synthesis 3) Increased ROS production 4) Organelle Swelling/Rupture |
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Coincidental Changes in Apoptotic Susceptibility in IMF/SS MTC with Denervation |
Huge increase in ROS from SS VS small change in IMF ~> MnSOD stayed higher longer in IMF (more stable population of MTC) |
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Apoptosis as contributing factor in cell death |
AIF: Elevated >5 days and plateau'd Casp-3: Significant increase in 8 days BAX:Bcl-2 - Inverse relationship (More pore opening vs less poor inhibition) |
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mtPTP Kinetics with Denervation |
Vmax - speed of poor opens faster Vmax (t) - decreases = less time to re-open |
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ALWAY Exercise's Protective Effects Against Apoptosis |
Bcl-2 increase 50% ~> + inhibition BAX not significant |
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YALNSHTEIN & HOOD Endurance Training on Apoptotic Susceptibility in Soleus (S) & Heart (H) |
S: BAX:Bcl-2 decreases as well as AIF H: BAX:Bcl-2 decrease as well as AIF EX Attenuates apoptotic signalling |
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ADHIHETTY CCA ON CytC Release (IMF/SS - MTC) |
1) Decrease BAX:Bcl-2 ~higher inhibition 2) Increase Vmax (t) ~pore closed more 3) Increased Cardiolipin ~CytC bound more |
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What 5 Factors Occur with Age? |
1) Decreased [MTC] + Function 2) Increased Apoptotic Susceptibility 3) Decreased Protein Import 4) Increased Sarcopenia 5) Decreased Exercise Adaptation |
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Sarcopenia |
1-2% >50 Years old i) decreased [MTC] ii) dysfunctional MTC (High ROS/Low Respiration) iii) increased MTC-Mediated Apoptosis |
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CONLEY Sarcopenia In The Muscle |
Decreased 1) oxidative capacity (p/gram muscle) 2) [MTC] vol/p/gram muscle 3) oxidative capacity (p/MTC) |
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CHABI & HOOD Biochemical Indices of [MTC] w/ Age In Soleus (S) // Plantaris (P) |
COX Activity: 30% reduction in S & P PGC1a Protein Levels: Decreased in both i) higher in S ~> more MTC |
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HUANG & HOOD Age on Processing & Import of Matrix Proteins |
No difference between young/old on import Difference in CAPACITY ~> Cytsolic changes in old degrade pre-cursor proteins faster |
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MTC & ROS Production - Causes |
1) mtDNA Damage 2) Apoptotic Protein Release 3) Increased Pore opening |
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ROS Production & Anti-Oxidant Enzymes w/ Age |
ROS increases with age but no increase from [Anti-Oxidant Enz] |
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mtDNA Mutations in Aged Human Tissue |
Mutations/common deletions occur @ 60-70 Years of age BUT point mutations in mtDNA occur at 40-60 years of age PRIOR to mutations |
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Mutations in Aged muscle - COX & SDH |
Old muscle more COX negative so nucleus overcompensates with SDH expression |
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Aged Muscle Vs Young Muscle |
Endurance - Decreased Tension w/ increasing contraction time in old Strength - Max force lower on gram basis Sarcopenia - in rats (36months) higher ~except in Hypertrophy of heart |
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Aging Flow Explanation |
As you age you increase the MTC ROS production meaning there's more apoptotic protein release. The more proteins released the higher the mtDNA damage is which causes more ROS alongside a increase in Nuclear DNA fragmentation creating a positive feedback loop . Once your mtDNA is damaged it increases Nuclear damage, atrophying the whole muscle fiber and accounts for the decrease in muscle mass |
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Sarcopenia Contributions |
1) Loss of strength 2) Decreased metabolic rate 3) Decreased Aerobic Capacity 4) Decreased Functionality |
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Evaluating Fatigue in Old vs Young muscle with CCA |
~> both groups had lower fatigue in tension over time with CCA but young had GREATER improvement Old doesn't respond as well (1/2 fold as well) ~COX Activity: 15% vs 25% in young ~Protein Import: faster in young-CCA but no increase in old, just attenuates age-associated decline |
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CCA Induced Expression of MTC-BG Regulatory Proteins |
All increase in both young and old BUT Old show MUCH less adaptation than young |
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REZNICK AMPK in older CCA animals |
no significant different in old animals with increased AMPK activity |
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ROS Production and Exercise in Old Animals |
Exercise COMPLETELY relieves ROS stress in BOTH young/old |
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DNA Fragmentation & CCA in Old Animals |
2-3 fold decrease in Fragmentation in Old animals with CCA |
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CONCLUSION |
1) Aged Skeletal Muscle = reduced adaptive plasticity toward MTC-BG i) Reduced signalling ii) Reduced Gene transcription 2) CCA attenuates DNA Fragmentation 3) Old Muscle CAN adapt ~> Needs stronger stim/duration |
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Group 1 Resistance Exercise on MTC Function |
increased State 3 respiration increased resp capacity via higher uncoupling |
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Group 2 Acute Exercise Remodels MTC Membrane Interactions |
no change shape/size/structure Electron Density Contact Sites increased ~> (in IMF 93% vs 16% SS) ~> doesn't mean they fuse |
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Group 3 CamKII on MTC // Contractile |
Doesn't influence MTC ~> mTOR pathway Type II Myosin Heavy Chain influenced contractile ability |
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Group 4 AMPK - R419 Activity |
R419 improves glucose tolerance (AMPK Independent) improved exercise capacity (AMPK Dependent) improved insulin sensitivity (AMPK Independent) improved glucose |
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Group 5 Apoptosis/Necrosis & Muscle Fiber loss in Aged Rats |
3x more apoptotic factors in aged 9x more necrosis factors in aged 60% markers were related to Enzymatic Issues (ETC) Longer ETC issues = prone to atrophy tBid, PUMA, cleaved Casp-3 (APOP markers) c5b-9 & CD68 (Necrotic markers) Less COX ~> SDH compensation mtDNA mutations increases COX4 issues increasing APOP/Necrotic markers |
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Group 6 Mitophagy and EndoG |
Decreased mitophagy leaves sensitive mtPTP decreases Parking VDAC ratio --> endo g releases and kills |
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Group 7 Thyroid Hormone of Autophagy |
Decreased mTOR Increased mRNA PGC1a expression Increased AMPK Increased ROS |