Exercise-induced preconditioning in skeletal...
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Exercise-induced preconditioning in skeletal
muscles
Scott K. PowersDepartment of Applied Physiology
and Kinesiology
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1) Introductiondisuse muscle
atrophy
2) Ventilator-induced diaphragm dysfunction
3) Exercise-induced pre-conditioning against atrophy
ROAD TRIP
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Human Condition Resulting in Disuse
Muscle AtrophyAnimal model
Bed Rest
Limb Immobilization
Space Flight
Spinal Cord Injury
Hind-limb Suspension
Limb Immobilization
Hind-limb Suspension
Denervation/Spinal Cord Isolation
Mechanical Ventilation (Diaphragm inactivity)
Mechanical Ventilation
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Skeletal muscle protein balance and muscle sizeAtrophy Hypertrophy
Muscle
ProteinProtein synthesis
Protein degradation
Protein synthesis
Protein degradation
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Importance of maintaining healthy skeletal muscle mass
• Healthy muscles are essential for breathing and locomotion
• Muscle is an endocrine organ and myokines are potential regulators of other organs
• Mortality rate of many diseases are associated with functional status and mass of skeletal muscles
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1) Introduction to disuse muscle
atrophy
2) Ventilator-induced diaphragm dysfunction
3) Exercise-induced pre-conditioning against atrophy
ROAD TRIP
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Mechanical Ventilation (MV)MV is used clinically to maintain adequate pulmonary
gas exchange in patients who are incapable of maintaining sufficient alveolar ventilation
Common indications: Respiratory failure, heart failure, neuromuscular diseases, drug overdoses, spinal cord injury, and surgery/post-surgical recovery
Prolonged MV results in inspiratory muscle weakness
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Diaphragm is the principal muscle of inspiration in all
mammals
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Rat model of mechanical ventilation
Hudson 2010
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MV-induced diaphragmatic atrophy (18 hours)
0
200
400
600
800
1000
1200
Total Dia Costal Dia Soleus
ControlMV
Mass (mg)
*
** P<0.05
Shanely et al. 2002~∆-20%
∆ -0%
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Prolonged MV promotes time-dependent decrease in diaphragmatic
specific force
Powers et al. 2002
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Prolonged MV results in rapid diaphragmatic
atrophy in humans
Levine et al. NEJM (2008)
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MV-induced diaphragmatic atrophy and contractile dysfunction is termed:
Ventilator-induced diaphragm dysfunction
(VIDD)
Why study VIDD?• ~30% patients exposed to
prolonged MV experience difficult weaning
• Failure to wean results in extended stays in ICU
• Diaphragmatic weakness predicted to be major risk factor for difficult weaning
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Mechanisms responsible for the rapid
development of ventilator-induced
diaphragm atrophy?
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Fractional Rate of Mixed Muscle Protein Synthesis-diaphragm
SB 6 MV 6 SB 12 MV 12 SB 18 MV 18
% /
hr
0.00
0.05
0.10
0.15
0.20
0.25
0.30
‡
‡
**
*
-30% -26% -29%
Shanely et al. 2004
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Controlled MV and diaphragmatic proteolysis (18 hours)
nmol
Tyr
osin
e/m
g/2
hr
0.000
0.075
0.150
0.225
0.300
CON MV
*
+28%
Shanely et al. 2002
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1) Introduction
2) Ventilator-induced diaphragm dysfunction
ROAD TRIP
3) Exercise-induced pre-conditioning against
atrophy
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Strategies to protect against VIDD?• Increase diaphragmatic antioxidant
capacity• Increase mitochondrial biogenesis
and maintain healthy mitochondrial pool
• Increase abundance of stress proteins in diaphragm
Regular bouts of endurance exercise has been shown to achieve all of these goals in trained skeletal muscle
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Does exercise training result in diaphragmatic adaptations that
protect against VIDD?Two exercise experiments
1) Continuous aerobic exercise (Endurance exercise) 10 days of exercise training (60 min/day, ~70% VO2max)
2) High intensity interval training (HIIT)10 days of HIIT training (60s x 5 intervals, ~100% VO2max)
MV initiated 24 hours after last exercise bout
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Diaphragm fiber cross sectional area (CSA)
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Exercise training maintains mitochondrial function and decreases ROS production during MV
Smuder et al. J Appl Physiol 2012 § MV vs. all groups
75
5037
4-HNE
α-tubulin
kDa
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High intensity interval training does not prevent mechanical ventilation-
induced diaphragmatic atrophy
Smuder et al (2012)
** * *
* *
Type I Type IIa Type IIb/x
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*P<0.05, MV significantly different from control within strain
Diaphragm muscle fibers cross sectional areas
Sollanek et al. 2015
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Ohlendieck 2011, Skeletal muscleProteomics approach
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High intrinsicaerobic capacity
Endurance exercisetraining
High intensity Interval training
146
1910
2112
157
HSP72
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Experimental strategy
Phase 1- Transfect and overexpress single protein of interest in diaphragm;Determine if overexpression of single protein is sufficient to protect against VIDDPhase 2- Gene silencing to prevent exercise-induced expression of protein;Determine if exercise-induced expression of protein is required to protect against VIDD
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Rib Cage
Xypoid Process
DiaphragmInjectionSite
Diaphragm AAV9 injections
GFP
SHAM
Smuder et al. Hum Gene Ther Methods 2013
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HSP72 overexpression in the diaphragm
& sig diff vs. CON and MV
72
kDa
100
α-tubulin
Smuder et al. (unpublished)
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HSP72 overexpression protects against MV-induced diaphragm atrophy
CON MV MV‐HSP
Smuder et al. (unpublished) † MV vs. CON and CON-HSP§ MV vs. CON, CON-HSP and MV-HSP
CON‐HSP
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What happens to exercise-induced protection against VIDD when exercise-mediated expression of HSP 72 is prevented?
Work in progress…..
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Summary1. MV-induced diaphragmatic atrophy
occurs rapidly –major risk factor for difficult weaning
2. Endurance exercise training protects against MV-induced diaphragmatic atrophy in rodents-exercise is an experimental tool for treatment discovery
3. Exercise-induced increases in diaphragmatic HSP72 may play a key role in exercise-induced preconditioning of diaphragm
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AcknowledgementsUniversity of FloridaJoe McClung, PhDAndy Shanely, PhDAshley Smudder, MSDarin Van Gammeren, PhDDarin Falk, PhDMelissa Deering, PhDKeith DeRuisseau, PhDAndreas Kavazis, PhDMatt Hudson, MSBrad Nelson, MSKisuk Min, MSErin Talbert, BSOh-Sung Kwon, MSKurt Sollanek, PhDMichael Wiggs, PhDUniversity of PennsylvaniaSanford Levine, MDCornell UniversityHazel Szeto, MD, PhDUC-IrvineCatherine Sassoon, MD
Acknowledgements(International)
Leuven UniversityMarc DeCramer, MD, PhDGhis Gayan-Ramirez, PhDKaren Maes, PhD
University of QueenslandJeff Coombes, PhD
Hacepette UniversityHaydar Demirel, MD, PhDMurat Zergeroglu, MD, PhD
Jutendo UniversityHisashi Naito, PhD
Porto UniversityJose Duarte, MD, PhD
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Thank you for your attention
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Special thanks to: