AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

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AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE? Dr Esther Barreiro, MD, PhD Muscle & Respiratory System Research Unit,IMIM-Hospital del Mar, Parc de Salut Mar, UPF, PRBB,CIBERES, Barcelona, Spain

description

Barcelona-Boston Lung Conference

Transcript of AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

Page 1: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

AIRWAYS, BONES & MUSCLES:DISEASE OR DISUSE?

Dr Esther Barreiro, MD, PhD

Muscle & Respiratory System Research Unit,IMIM-Hospital del Mar, Parc de Salut Mar, UPF,

PRBB,CIBERES, Barcelona, Spain

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CIGARETTE SMOKECOPD

AIRWAYS & LUNGS

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PREVALENCE OF COPD WORLWIDEPrevalence of COPD:- Higher in smokers & exsmokers than in non-smokers- In people > 40 yrs, highest prevalence > 60 yrs - In men than in women- Prevalence ranges from 7.8%-19.7%

- The Burden of Obstructive Lung Diseases Program (BOLD) has documented a substantial prevalence (3-11%) of COPD among never-smokers (!)

COPD will be the third leading cause of death worlwide by 2020!!!

www.goldcopd.org

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CS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESS

Nicotine, cadmium, benzopyrene, reactive oxygen species Nicotine, cadmium, benzopyrene, reactive oxygen species (ROS) inducers, and oxidants are the main components (ROS) inducers, and oxidants are the main components involved in the involved in the toxicitytoxicity of of cigarette smokecigarette smoke (CS). (CS).

It is generally accepted that the large number of It is generally accepted that the large number of oxidantsoxidants contained in the contained in the CSCS induce induce adverse efffects on tissuesadverse efffects on tissues through through oxidative damageoxidative damage of key biological structures. of key biological structures.

On the other hand, CS-induced activation of On the other hand, CS-induced activation of inflammatory inflammatory

cellscells will further contribute to will further contribute to enhanced oxidant productionenhanced oxidant production. .

Nicotine, cadmium, benzopyrene, reactive oxygen species Nicotine, cadmium, benzopyrene, reactive oxygen species (ROS) inducers, and oxidants are the main components (ROS) inducers, and oxidants are the main components involved in the involved in the toxicitytoxicity of of cigarette smokecigarette smoke (CS). (CS).

It is generally accepted that the large number of It is generally accepted that the large number of oxidantsoxidants contained in the contained in the CSCS induce induce adverse efffects on tissuesadverse efffects on tissues through through oxidative damageoxidative damage of key biological structures. of key biological structures.

On the other hand, CS-induced activation of On the other hand, CS-induced activation of inflammatory inflammatory

cellscells will further contribute to will further contribute to enhanced oxidant productionenhanced oxidant production. .

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Cigarette smokeCigarette smoke+ +

Air polutionAir polution

ROSROS

CytokinesCytokines

OXIDATIVE STRESSOXIDATIVE STRESSOXIDATIVE STRESSOXIDATIVE STRESS

ONOOONOO--(peroxynitrite)(peroxynitrite)

ONOOONOO--(peroxynitrite)(peroxynitrite)

((OO22--))

NITROSATIVE STRESSNITROSATIVE STRESSNITROSATIVE STRESSNITROSATIVE STRESS

NONO(nitric oxide)(nitric oxide)

myeloperoxidases

myeloperoxidases

Deleterious effects on tissuesDeleterious effects on tissuesDeleterious effects on tissuesDeleterious effects on tissues

Lung oxidative and nitrosative stress induced by CS and air polutionLung oxidative and nitrosative stress induced by CS and air polutionLung oxidative and nitrosative stress induced by CS and air polutionLung oxidative and nitrosative stress induced by CS and air polution

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CS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESS

Morrow et al. N Eng J Med 1995

Lipid peroxidation Lipid peroxidation markers markers

Lipid peroxidation Lipid peroxidation markers markers

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CS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESS

Park et al. Free Radic Biol Med 1998

Rats exposed to CSfor 30 days

Rats exposed to CSfor 30 days

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CS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESSCS-INDUCED OXIDATIVE STRESS

Ardite et al. Respir Med 2006

Guinea pigsGuinea pigs

Acute CS exposureAcute CS exposure

7 cigarettes7 cigarettes

Guinea pigsGuinea pigs

Acute CS exposureAcute CS exposure

7 cigarettes7 cigarettes

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Montes de Oca et al. Chest 2008

Cigarette smoke & muscle structure Cigarette smoke & muscle structure Cigarette smoke & muscle structure Cigarette smoke & muscle structure

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Wüst et al. Eur J Appl Physiol 2008

Cigarette smoke & muscle function Cigarette smoke & muscle function Cigarette smoke & muscle function Cigarette smoke & muscle function

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Cigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weight

Ardite et al. Respir Med 2006

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Cigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weight

Barreiro et al. Am J Respir Crit Care Med 2010

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COPD&

BONES

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Imbalance between osteoblast & osteoclast activity

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Prevalence of osteoporosis in COPD

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Risk factors of osteoporosis in COPD

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Clinical guidance to treat osteoporosis in COPD

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Routine chest CT

Measured using DEXA

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Changes in BMD, lung function, … & exacerbations

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Annual change in thoracic vertebral BMD & exacerbations

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COPD&

MUSCLES

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EVIDENCE OF MUSCLE DYSFUNCTIONEVIDENCE OF MUSCLE DYSFUNCTION

MIP MEP HG QUAD0

50

100

150

% p

red

.

Gosselink et al. AJRCCM 1996; 153. 976-80

Muscle dysfunction in COPDMuscle dysfunction in COPDMuscle dysfunction in COPDMuscle dysfunction in COPD Force & Force & Endurance Endurance Force & Force & Endurance Endurance

COPD HEALTHY

QoL QoL Exercise toleranceExercise tolerance

CachexiaCachexiaMuscle lossMuscle loss CachexiaCachexiaMuscle lossMuscle loss

respiratory muscles limb muscles

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Seymour et al. Eur Respir J 2010; 36: 81-88

PREVALENCE OF QUADRICEPS DYSFUNCTION IN COPD PATIENTS

PREVALENCE OF QUADRICEPS DYSFUNCTION IN COPD PATIENTS

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QUADRICEPS WEAKNESS & DISEASE SEVERITY IN COPD PATIENTS

QUADRICEPS WEAKNESS & DISEASE SEVERITY IN COPD PATIENTS

Seymour et al. Eur Respir J 2010; 36: 81-88

Quadriceps weakness exists in the absenceof severe airflow obstruction!

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QUADRICEPS WEAKNESS PREDICTS MORTALITY IN COPD PATIENTS

QUADRICEPS WEAKNESS PREDICTS MORTALITY IN COPD PATIENTS

Midthigh muscle cross sectional area is a better predictor of mortality than BMI in COPD patients

QMVC is simple and provides prognosticinformation than other parameters

(age, BMI, and FEV1) in COPD

Marquis et al. AJRCCM 2002; 166: 809-813. Swallow et al. Thorax 2007; 62: 115-120.

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Activity & type of muscle!!!

Activity & type of muscle!!!

Oxidative stress

Comorbidities

Hypercapnia

Drugs

Inflammation

Hypoxia

Malnutrition

Genetic susceptibility Cigarette smoking

Deconditioning

ApoptosisProteolysis

MUSCLE DYSFUNCTION IN COPD MUSCLE DYSFUNCTION IN COPD

Epigenetics

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Protein anabolism

Signaling pathwaysProtein anabolism

Signaling pathways

Signaling pathwaysProtein catabolismSignaling pathwaysProtein catabolism

Muscle proteins

SynthesisSynthesisSynthesisSynthesis DegradationDegradationDegradationDegradation

IMBALANCE BETWEEN PROTEIN SYNTHESIS & DEGRADATION

MUSCLE MASS LOSS

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Enhanced muscle proteolysis

Diaphragm, stable COPD patients:

Ottenheijm et al. Am J Respir Crit Care Med 2006

Testelmans et al. Eur Respir J 2010

Diaphragm, stable COPD patients:

Ottenheijm et al. Am J Respir Crit Care Med 2006

Testelmans et al. Eur Respir J 2010

Vastus lateralis, stable COPD patients:

Doucet et al. Am J Respir Crit Care Med 2007

Plant et al. Am J Respir Cell Mol Biol 2010

Fermoselle et al. Eur Respir J 2012, 40: 851-62

Vastus lateralis, stable COPD patients:

Doucet et al. Am J Respir Crit Care Med 2007

Plant et al. Am J Respir Cell Mol Biol 2010

Fermoselle et al. Eur Respir J 2012, 40: 851-62

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Vastus lateralis, COPD patients during exacerbations:

Crul et al. Cell Physiol Biochem 2010

Vastus lateralis, COPD patients during exacerbations:

Crul et al. Cell Physiol Biochem 2010

Vastus lateralis, stable COPD patients:

Troosters et al. Am J Respir Crit Care Med 2010

Vogiatzis et al. Eur Respir J 2010

Vastus lateralis, stable COPD patients:

Troosters et al. Am J Respir Crit Care Med 2010

Vogiatzis et al. Eur Respir J 2010 After general training

Enhanced muscle proteolysis

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A FEW RESULTS

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Addition of a single electron to the oxygen molecule through a redution process leads to the sequential production of a series of reactive molecules

such as O2-, H2O2, and OH.

OXIDATIVE STRESSOXIDATIVE STRESS Greater levels of ROS production than those Greater levels of ROS production than those

normally neutralized by intracellular antioxidant defensesnormally neutralized by intracellular antioxidant defenses

Oxidative damage to other cellular components of the cell:- peroxidation of membrane phospholipids- modification of nuclear DNA- alteration of proteins

Enzymatic changesEnzymatic changes ProteolysisProteolysis

REACTIVE OXYGEN SPECIES

ApoptosisApoptosis

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LIMB MUSCLES: VASTUS LATERALIS

Open muscle biopsy techniqueOpen muscle biopsy technique

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0

0.25

0.75

0

0.25

0.50

0.75

0.50

0

0.4

0.8

1.2React

ive c

arb

on

yl g

rou

ps

(OD

, a.u

.)

Mn

-su

pero

xid

e d

ism

uta

se (

OD

, a.u

.)

Controls

COPD patients

Cu

Zn

-su

pero

xid

e d

ism

uta

se (

OD

, a.u

.) Controls

COPD patients

*

*

***†††

n.s.

*n.s.

Muscle-wasted

Muscle-wastedNon-wasted

Non-wasted

REDOX BALANCE IN QUADRICEPS

Fermoselle et al. Eur Respir J 2012, 40: 851-62

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20 30 40 50

.5

.6

.7

.8

.9

1.0

1.1

1.2

r= -0.648p=0.043

10

QMVC, kg

React

ive c

arb

on

yl g

rou

ps,

nm

ol/m

g

4 6 8 10 12 14

.6

.8

1.0

1.2

r= -0.664p=0.026

Q twitch, kg

React

ive c

arb

on

yl g

rou

ps,

nm

ol/m

g

Muscle protein oxidation – Quadriceps muscle forceMuscle protein oxidation – Quadriceps muscle force

E. Barreiro et al. Thorax 2008; 63: 100-107

OXIDATIVE STRESS: CLINICAL IMPLICATIONS

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20

40

60

80

2 3 4 5 6 7 8 9

Total protein carbonylation/GAPDH immunoreactivity

WR

max

, % p

red

r=-0.539p=0.038

20

40

60

80

100

VO

2max

, % p

red

2 3 4 5 6 7 8 9

Total protein carbonylation/GAPDH immunoreactivity

r=-0.643p=0.010

E. Barreiro et al. Thorax 2009; 64: 13-19

Muscle protein oxidation – Exercise capacityMuscle protein oxidation – Exercise capacity

OXIDATIVE STRESS: CLINICAL IMPLICATIONS

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OXIDATIVELY MODIFIED PROTEINS

Phosphocreatine (PCr) + ADP + H+Phosphocreatine (PCr) + ADP + H+ ATP + creatineATP + creatine

CO2 + H2O CO2 + H2O HCO3- + H+HCO3- + H+

CK

AC

Vastus lateralisVastus lateralis

E. Barreiro et al. Am J Respir Cell Mol Biol 2005

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0

2

4

6

8

10

12

14

Enolase Aldolase Creatine kinase

Carbonicanhydrase-3

ActinGAPDH

ATPsynthase

C C S C C SC S C S C SCOPDCOPD COPDCOPD COPD COPD COPDSS

React

ive c

arb

onyl gro

ups

(OD

, a.u

.) *

***

***

**

***

**

***

*

***

Barreiro et al. AJRCCM 2010; 182: 477-488.

Oxidatively modified proteins in Smokers & COPD

Vastus lateralisVastus lateralis

Carbonylated Proteins: Controls, Smokers & COPDCarbonylated Proteins: Controls, Smokers & COPD

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MUSCLE FIBER ATROPHY

Fermoselle et al. Eur Respir J 2012, 40: 851-62

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MUSCLE FIBER ATROPHY

Severe COPD&

Cachexia

Fermoselle et al. Eur Respir J 2012, 40: 851-62

Page 47: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

Controls Non-wasted COPD Muscle-wasted COPD

SUPEROXIDE ANION WITHIN MYONUCLEI

Fermoselle et al. Eur Respir J 2012, 40: 851-62

0

20

40

Controls Non-wastedMuscle-wasted%O

2-

in m

yon

ucl

ei

*** ***

COPD patients

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0

0.2

0.4

0.6

0.8

1

0

0.1

0.2

0.3

0

0.2

0.4

0

0.2

0.4

0.6

0

0.5

1

1.5

Tota

l u

biq

uit

inate

d p

rote

ins

(O

D,

a.u

.)2

0S

pro

teaso

me s

ub

un

it C

8

(OD

, a.u

.)

Ub

iqu

itin

-con

jug

ati

ng

E2

14k (

OD

, a.u

.)U

biq

uit

in lig

ase

atr

og

in-1

(O

D,

a.u

.)U

biq

uit

in lig

ase

MU

RF-

1 (

OD

, a.u

.)

ControlsCOPD patients

Controls

COPD patients

n.s.

*

n.s.

n.s.

* *

p=0.08 *

n.s.

n.s.

Muscle-wasted

Muscle-wasted

Non-wasted

Non-wasted

Proteolysis: Ubiquitin-proteasome system

Fermoselle et al. Eur Respir J 2012, 40: 851-62

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MyH

C c

on

ten

t (O

D,

a.u

.)

0

0.1

0.2

0.3

0

0.05

0.1

Controls

COPD patients

Carb

on

yla

ted

MyH

C (

OD

, a.u

.)

*†

**

*

Muscle-wastedNon-wasted

n.s.

MYOSIN CONTENT & OXIDATION

MyHC oxidation

MyHC content

Fermoselle et al. Eur Respir J 2012, 40: 851-62

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HUMAN DIAPHRAGM

ThoracotomyThoracotomy

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Tot

al C

arb

onyl

gro

up

for

mat

ion

(O

D, a

.u.)

SEVERECOPD

CONTROLS

1.0

0.5

0

1.5 *

MODERATECOPD

ns

80604020

1.6

1.2

0.8

0.4

r = - 0.734p < 0.01

FEV1 (% pred.)T

otal

Car

bon

yl g

rou

p f

orm

atio

n (

OD

, a.u

.)

Barreiro et al. Am J Respir Crit Care Med 2005

OXIDATIVE STRESS

Oxidized proteins - DiaphragmsOxidized proteins - Diaphragms

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MW (KDa)

98

64

50

36

30

3 10pH

MW (KDa)

98

64

50

36

30

3 10pH 3 10pH 3 10pH

Control

Severe COPD

Moderate COPDControl Moderate COPD

Severe COPD Severe COPD Severe COPD

Creatine kinase isoforms

Carbonic anhydraseisorfoms

α-1 actinCreatine kinase

isoforms

Carbonic anhydraseisorfoms

α-1 actin

Creatine kinase isoforms

Carbonic anhydraseisorfoms

α-1 actin Creatine kinase isoforms

Carbonic anhydraseisorfoms

α-1 actin

Creatine kinase isoforms

Carbonic anhydraseisorfoms

α-1 actinCreatine kinase

isoforms

Carbonic anhydraseisorfoms

α-1 actin Creatine kinase isoforms

Carbonic anhydraseisorfoms

α-1 actin

Creatine kinase isoforms

Carbonic anhydraseisorfoms

α-1 actin

OXIDATIVELY MODIFIED PROTEINS

Marin-Corral et al. Eur Respir J 2009; 33: 1309-1319

DiaphragmsDiaphragms

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0

0.5

1

Controls Severe COPDModerate COPDMyH

C c

arb

on

yla

tion

/ G

APD

H

***n.s.***

36GAPDH

Controls Severe COPDModerate COPD

250

MW (KDa)

MyHC content & oxidation

Marin-Corral et al. Eur Respir J 2009.

0

0.5

1

1.5

Controls Severe COPDModerate COPDM

yH

C c

onte

nt

/ G

APD

H

***n.s.***

250

Myosin Heavy Chain

Controls Severe COPDModerate COPD

36GAPDH

+ve

MW (KDa)

Diaphragms, stable COPD

MyHC oxidation MyHC content

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TNF-αIl-1β

IL12IL8

IFN-

IL4/IL13

IL-1Ra

TGFβIL10

PROINFLAMMATORY

ANTI-INFLAMMATORY

CYTOKINES

INFLAMMATIONINFLAMMATION

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COPDCTL

TN

F-alp

ha, p

g/m

L

40

30

20

10

0

p=0.04

50

COPDCTL

1.0

0.75

0.50

0.25

0

p=0.0081.25

TN

F-alp

ha R

II, p

g/m

L

Cytokines in the vastus lateralis of severe COPD patients

Cytokines in the vastus lateralis of severe COPD patients

E. Barreiro et al. Thorax 2008; 63: 100-107

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leucocyte macrophage

Cellular inflammationCellular inflammation

Patients with COPD, Vastus lateralisPatients with COPD, Vastus lateralisPatients with COPD, Vastus lateralisPatients with COPD, Vastus lateralis

Barreiro et al. J Appl Physiol 2011; 111: 808-817

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Barreiro et al. J Appl Physiol 2011; 111: 808-817

Cellular inflammationCellular inflammation

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Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94.

SYSTEMIC INFLAMMATIONSYSTEMIC INFLAMMATION

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200

250

300

350

400

450

500

Blo

od T

NF-a

lpha levels

, (p

g/m

l) p=0.002

Ctl

CS

SYSTEMIC INFLAMMATION IN SMOKING MICESYSTEMIC INFLAMMATION IN SMOKING MICESYSTEMIC INFLAMMATION IN SMOKING MICESYSTEMIC INFLAMMATION IN SMOKING MICE

Barreiro et al. Respir Physiol Neurobiol 2012.

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EXERCISE:EXERCISE:Muscles in COPDMuscles in COPD

EXERCISE:EXERCISE:Muscles in COPDMuscles in COPD

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Endurance Exercise TrainingProtein tyrosine nitration

Endurance Exercise TrainingProtein tyrosine nitration

p = 0.093

p = 0.029p = 0.079

Blo

od

Pro

tein

Nitr

atio

n (

nM

)

1.00

1.20

1.40

1.60

1.80

2.00

2.20

2.40

2.60

PreControls

PostControls

PreCOPD

PostCOPD

Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94.

After exercise training, 8 weeks

BloodBlood

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Endurance Exercise TrainingMuscle protein tyrosine nitration

Endurance Exercise TrainingMuscle protein tyrosine nitration

After exercise training, 8 weeks

p = 0.061p = 0.155

p = 0.021

Mu

scle

Pro

tein

Nitr

atio

n (

O.D

, a

.u)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

PreControls

PostControls

PreCOPD

PostCOPD

Vastus lateralisVastus lateralis

Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94.

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Chronic exposure to CS

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Time 0Time 0 3 months3 months 6 months6 months

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

4 months4 months

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

7 cig/day CS, n=7Control, n=7

7 cig/day CS, n=7Control, n=7

7 cig/day CS, n=7Control, n=7

7 cig/day CS, n=7Control, n=7

7 cig/day CS, n=7Control, n=7

7 cig/day CS, n=7Control, n=7

EXPOSURE TIMEEXPOSURE TIMEEXPOSURE TIMEEXPOSURE TIME

Guinea pigs chronically exposed to CSGuinea pigs chronically exposed to CSGuinea pigs chronically exposed to CSGuinea pigs chronically exposed to CS

Barreiro et al. Am J Respir Crit Care Med 2010.

GUINEA PIG EXPOSED TO CIGARETTE SMOKE

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0

2

4

6

8

10

C S C S C S C S C SEnolase Aldolase Creatine

kinaseActinATP

synthase

**

0

2

4

6

8

10

12

14

C S C S C S C S C SEnolase Aldolase Creatine

kinaseActinATP

synthase

***

C S C S C S C S C S C S C S C SEnolaseAldolase Creatine

kinaseActinGAPDH ATP

synthaseTriosephosphateisomerase

Tropomyosin

***

*

**

**

*

C S C S C S C S C S C S C S C SEnolaseAldolase Creatine

kinaseActinGAPDH ATP

synthaseTriosephosphateisomerase

Tropomyosin

******

*

***

***

*

React

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eact

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React

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eact

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Diaphragms, 3 months

Gastrocnemius, 6 monthsGastrocnemius, 3 months

Diaphragms, 6 months

0

4

8

12

16

20

0

2

4

6

8

10

Carbonylated ProteinsCarbonylated Proteins

Barreiro et al. Am J Respir Crit Care Med 2010.

GUINEA PIG EXPOSED TO CIGARETTE SMOKE

Page 66: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

MICE EXPOSED TO CIGARETTE SMOKE

Barreiro et al. Respir Physiol Neurobiol 2012.

Time 0Time 0 6 months6 months

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

DiaphragmDiaphragmGastrocnemiusGastrocnemius

Lungs

2 cig/day CS, n=13Control, n=9

2 cig/day CS, n=13Control, n=9

Mice chronically exposed to CSMice chronically exposed to CSMice chronically exposed to CSMice chronically exposed to CS

EXPOSURE TIMEEXPOSURE TIMEEXPOSURE TIMEEXPOSURE TIME

Male AKR/J miceMale AKR/J mice

Page 67: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

React

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1.0

2.0

3.0

Ctl

CS Ctl

CS

diaphragm gastrocnemius

p=0.009

p=0.017

Protein CarbonylationProtein Carbonylation

MICE EXPOSED TO CIGARETTE SMOKE

Barreiro et al. Respir Physiol Neurobiol 2012.

Page 68: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

IDENTIFICATION OF OXIDIZED PROTEINSIDENTIFICATION OF OXIDIZED PROTEINS

Barreiro et al. Respir Physiol Neurobiol 2012.

Page 69: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

Environment,Triggers, Signaling pathways

Apoptosis Proteolysis

Muscle & bone loss

Locomotor dysfunction & fractures QoL

COPD muscle & bone dysfunction: Present & Future

AutophagyEpigenetics Senescence

Targets

Targets

Page 70: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

Questions that still need to be Questions that still need to be addressed?addressed?

Questions that still need to be Questions that still need to be addressed?addressed?

To target patients at earlier stages of their To target patients at earlier stages of their diseasedisease

To identify “common” molecular To identify “common” molecular markers/mechanisms of muscle and bone loss markers/mechanisms of muscle and bone loss and dysfunctionand dysfunction

To explore the potential reversibility induced by To explore the potential reversibility induced by exercise +/- nutritional support on muscle mass exercise +/- nutritional support on muscle mass & bone density loss and dysfunction& bone density loss and dysfunction

To elucidate the specific contribution of To elucidate the specific contribution of disusedisuse as opposed to myopathy (?) as opposed to myopathy (?) animal models? animal models?

To evaluate the specific role of oxygen To evaluate the specific role of oxygen metabolism & mitochondria, especially in metabolism & mitochondria, especially in muscles muscles

Page 71: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

Large-scale clinical studies conducted Large-scale clinical studies conducted on on

COPD patients & healthy controls COPD patients & healthy controls

How can we try to answer all these questions?

Molecular & Cellular analyses fromMolecular & Cellular analyses fromdifferent compartmentsdifferent compartments

Translational Research

* Specimens from patients* Animal models* In vitro studies

Page 72: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

ACKNOWLEDGMENTSACKNOWLEDGMENTS

Page 73: AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

THANK YOU!THANK YOU!