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
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
CIGARETTE SMOKECOPD
AIRWAYS & LUNGS
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
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. .
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
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
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
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
Montes de Oca et al. Chest 2008
Cigarette smoke & muscle structure Cigarette smoke & muscle structure Cigarette smoke & muscle structure Cigarette smoke & muscle structure
Wüst et al. Eur J Appl Physiol 2008
Cigarette smoke & muscle function Cigarette smoke & muscle function Cigarette smoke & muscle function Cigarette smoke & muscle function
Cigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weight
Ardite et al. Respir Med 2006
Cigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weightCigarette smoke & body weight
Barreiro et al. Am J Respir Crit Care Med 2010
COPD&
BONES
Imbalance between osteoblast & osteoclast activity
Prevalence of osteoporosis in COPD
Risk factors of osteoporosis in COPD
Clinical guidance to treat osteoporosis in COPD
Routine chest CT
Measured using DEXA
Changes in BMD, lung function, … & exacerbations
Annual change in thoracic vertebral BMD & exacerbations
COPD&
MUSCLES
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
Seymour et al. Eur Respir J 2010; 36: 81-88
PREVALENCE OF QUADRICEPS DYSFUNCTION IN COPD PATIENTS
PREVALENCE OF QUADRICEPS DYSFUNCTION IN COPD PATIENTS
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!
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.
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
Protein anabolism
Signaling pathwaysProtein anabolism
Signaling pathways
Signaling pathwaysProtein catabolismSignaling pathwaysProtein catabolism
Muscle proteins
SynthesisSynthesisSynthesisSynthesis DegradationDegradationDegradationDegradation
IMBALANCE BETWEEN PROTEIN SYNTHESIS & DEGRADATION
MUSCLE MASS LOSS
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
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
A FEW RESULTS
…
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
LIMB MUSCLES: VASTUS LATERALIS
Open muscle biopsy techniqueOpen muscle biopsy technique
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
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
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
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
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
MUSCLE FIBER ATROPHY
Fermoselle et al. Eur Respir J 2012, 40: 851-62
MUSCLE FIBER ATROPHY
Severe COPD&
Cachexia
Fermoselle et al. Eur Respir J 2012, 40: 851-62
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
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
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
HUMAN DIAPHRAGM
ThoracotomyThoracotomy
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
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
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
TNF-αIl-1β
IL12IL8
IFN-
IL4/IL13
IL-1Ra
TGFβIL10
PROINFLAMMATORY
ANTI-INFLAMMATORY
CYTOKINES
INFLAMMATIONINFLAMMATION
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
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
Barreiro et al. J Appl Physiol 2011; 111: 808-817
Cellular inflammationCellular inflammation
Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94.
SYSTEMIC INFLAMMATIONSYSTEMIC INFLAMMATION
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.
EXERCISE:EXERCISE:Muscles in COPDMuscles in COPD
EXERCISE:EXERCISE:Muscles in COPDMuscles in COPD
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
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.
Chronic exposure to CS
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
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
ive c
arb
on
yl g
rou
ps
(OD
, a.u
.)R
eact
ive c
arb
on
yl g
rou
ps
(OD
, a.u
.)
React
ive c
arb
on
yl g
rou
ps
(OD
, a.u
.)R
eact
ive c
arb
on
yl g
rou
ps
(OD
, a.u
.)
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
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
React
ive c
arb
onyl gro
ups
(OD
, a.u
.)
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.
IDENTIFICATION OF OXIDIZED PROTEINSIDENTIFICATION OF OXIDIZED PROTEINS
Barreiro et al. Respir Physiol Neurobiol 2012.
Environment,Triggers, Signaling pathways
Apoptosis Proteolysis
Muscle & bone loss
Locomotor dysfunction & fractures QoL
COPD muscle & bone dysfunction: Present & Future
AutophagyEpigenetics Senescence
Targets
Targets
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
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
ACKNOWLEDGMENTSACKNOWLEDGMENTS
THANK YOU!THANK YOU!