Dr Esther Barreiro, MD, PhD
Muscle & Respiratory System Research Unit,IMIMHospital del Mar, Parc de Salut Mar, UPF,
PRBB,C...
CIGARETTE SMOKE
COPD
AIRWAYS & LUNGS
PREVALENCE OF COPD WORLWIDE
Prevalence of COPD:
- Higher in smokers & exsmokers
than in non-smokers
- In people > 40 yrs, ...
CS-INDUCED OXIDATIVE
CS-INDUCED OXIDATIVE
STRESS
STRESS

• Nicotine, cadmium, benzopyrene, reactive oxygen species
(ROS) i...
ng oxidative and nitrosative stress induced by CS and air polutio
ng oxidative and nitrosative stress induced by CS and ai...
CS-INDUCED OXIDATIVE STRESS
CS-INDUCED OXIDATIVE STRESS
Lipid peroxidation markers
Lipid peroxidation markers

Morrow et a...
CS-INDUCED OXIDATIVE STRESS
CS-INDUCED OXIDATIVE STRESS

Rats exposed to CS
for 30 days

Park et al. Free Radic Biol Med 1...
CS-INDUCED OXIDATIVE STRESS
CS-INDUCED OXIDATIVE STRESS
Guinea pigs
Guinea pigs
Acute CS exposure
Acute CS exposure
7 ciga...
Cigarette smoke & muscle
Cigarette smoke & muscle
structure
structure

Montes de Oca et al. Chest 2008
Cigarette smoke & muscle
Cigarette smoke & muscle
function
function

Wüst et al. Eur J Appl Physiol 2008
Cigarette smoke & body weight
Cigarette smoke & body weight

Ardite et al. Respir Med 2006
Cigarette smoke & body weight
Cigarette 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 DYSFUNCTION
EVIDENCE OF MUSCLE DYSFUNCTION
Muscle dysfunction in COPD

↓ Force & ↓ Endurance

± Cachexi...
PREVALENCE OF QUADRICEPS
PREVALENCE OF QUADRICEPS
DYSFUNCTION IN COPD PATIENTS
DYSFUNCTION IN COPD PATIENTS

Seymour et al...
QUADRICEPS WEAKNESS & DISEASE
QUADRICEPS WEAKNESS & DISEASE
SEVERITY IN COPD PATIENTS
SEVERITY IN COPD PATIENTS

Quadricep...
QUADRICEPS WEAKNESS PREDICTS
QUADRICEPS WEAKNESS PREDICTS
MORTALITY IN COPD PATIENTS
MORTALITY IN COPD PATIENTS

Midthigh ...
MUSCLE DYSFUNCTION IN COPD
Activity & type
of muscle!!!
Hypoxia
Hypercapnia

Deconditioning
Inflammation
Epigenetics

Oxid...
MUSCLE MASS LOSS
IMBALANCE BETWEEN PROTEIN
SYNTHESIS & DEGRADATION

Muscle proteins

Synthesis
Synthesis

abolism
Protein ...
Enhanced muscle proteolysis
Diaphragm, stable COPD patients:
Diaphragm, stable COPD patients:
Ottenheijm et al. Am J Respi...
Enhanced muscle proteolysis
Vastus lateralis, COPD patients during exacerbations:
Vastus lateralis, COPD patients during e...
A FEW
RESULTS…
REACTIVE OXYGEN SPECIES
Addition of a single electron to the oxygen molecule through a redution
process leads to the seque...
LIMB MUSCLES: VASTUS LATERALIS
Open muscle biopsy technique
*
0.50

*

Mn-superoxide dismutase (OD, a.u.)

0.75

***
†††

0.75

0.50

0.25

n.s.

0

0.25

0

Controls

Non-wasted

Mu...
OXIDATIVE STRESS: CLINICAL IMPLICATIONS

Muscle protein oxidation – Quadriceps muscle force
r= -0.648
p=0.043

1.2

r= -0....
OXIDATIVE STRESS: CLINICAL IMPLICATIONS

Muscle protein oxidation – Exercise capacity

r=-0.539
p=0.038

r=-0.643
p=0.010
...
OXIDATIVELY MODIFIED PROTEINS
Vastus lateralis

Phosphocreatine (PCr) + ADP + H

+

CO2 + H2O
E. Barreiro et al. Am J Resp...
Oxidatively modified proteins in
Smokers & COPD
Carbonylated Proteins: Controls, Smokers & COPD
Carbonylated Proteins: Con...
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
SUPEROXIDE ANION WITHIN MYONUCLEI

Controls

Non-wasted COPD

Muscle-wasted COPD
%O2- in myonuclei

40

***

**
*

20

Fer...
n.s.

*

0.8
0.6

Ubiquitin-conjugating E214k (OD, a.u.)

1

0.4

*

*

p=0.08

*

n.s.

n.s.

0.2

0

0.2
0

0.3

n.s.

n...
MYOSIN CONTENT & OXIDATION

MyHC content (OD, a.u.)

0.3

n.s.

MyHC content

0.2

*
†

0.1

0

Carbonylated MyHC (OD, a.u...
HUMAN DIAPHRAGM
Thoracotomy
Thoracotomy
OXIDATIVE STRESS

1.5

*
ns

1.0

0.5

0
CONTROLS

MODERATE
COPD

Barreiro et al. Am J Respir Crit Care Med 2005

SEVERE
C...
OXIDATIVELY MODIFIED PROTEINS
Diaphragms

MW (KDa)
98
64

Creatine kinase
isoforms

α-1 actin

Creatine kinase
isoforms

α...
MyHC content & oxidation
Diaphragms, stable COPD
MW (KDa)

MW (KDa)

+ve

250

Myosin Heavy Chain

250
Controls

Moderate ...
INFLAMMATION
CYTOKINES
IL4/IL13
IL-1Ra

TNF-α

Il-1β

IL8

IL12

IFN-γ

TGFβ

IL10

ANTI-INFLAMMATORY
PROINFLAMMATORY
Cytokines in the vastus lateralis
of severe COPD patients

p=0.04
p=0.008

1.0

TNF-alpha R II, pg/mL

1.25

40

TNF-alpha...
Cellular
inflammation
Patients with COPD, Vastus lateralis
Patients with COPD, Vastus lateralis

leucocyte

Barreiro et al...
Cellular
inflammation

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

Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94.
SYSTEMIC INFLAMMATION IN SMOKING
SYSTEMIC INFLAMMATION IN SMOKING
MICE
MICE

Blood TNF-alpha levels, (pg/ml)

500

p=0.002...
EXERCISE:
Muscles in COPD
Endurance Exercise
Training
Blood
Protein tyrosine nitration

After exercise training, 8 weeks

p = 0.093

p = 0.079

p = ...
Endurance Exercise Training
Muscle protein tyrosine
nitration
Vastus lateralis

After exercise training, 8 weeks

p = 0.02...
Chronic exposure to CS
GUINEA PIG EXPOSED TO CIGARETTE SMOKE
Guinea pigs chronically exposed to CS
Guinea pigs chronically exposed to CS

EXPOSUR...
GUINEA PIG EXPOSED TO CIGARETTE SMOKE
10

Diaphragms, 6 months
Reactive carbonyl groups (OD, a.u.)

Reactive carbonyl grou...
MICE EXPOSED TO CIGARETTE SMOKE
Mice chronically exposed to CS
Mice chronically exposed to CS

EXPOSURE TIME
Time 0

6 mon...
MICE EXPOSED TO CIGARETTE SMOKE

Reactive carbonyl groups (OD, a.u.)

Protein Carbonylation
Protein Carbonylation
p=0.017
...
IDENTIFICATION OF OXIDIZED
PROTEINS

Barreiro et al. Respir Physiol Neurobiol 2012.
COPD muscle & bone dysfunction: Present & Future
Targets

Environment,Triggers, Signaling pathways

Targets

Apoptosis

Ep...
Questions that still need to be addressed?
Questions that still need to be addressed?
To target patients at earlier stages...
How can we try to answer all these
questions?
Large-scale clinical studies conducted on
COPD patients & healthy controls
T...
ACKNOWLEDGMENTS
THANK
YOU!
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
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AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

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AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

  1. 1. Dr Esther Barreiro, MD, PhD Muscle & Respiratory System Research Unit,IMIMHospital del Mar, Parc de Salut Mar, UPF, PRBB,CIBERES, Barcelona, Spain AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?
  2. 2. CIGARETTE SMOKE COPD AIRWAYS & LUNGS
  3. 3. PREVALENCE OF COPD WORLWIDE Prevalence 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
  4. 4. CS-INDUCED OXIDATIVE CS-INDUCED OXIDATIVE STRESS STRESS • Nicotine, cadmium, benzopyrene, reactive oxygen species (ROS) inducers, and oxidants are the main components involved in the toxicity of cigarette smoke (CS). • It is generally accepted that the large number of oxidants contained in the CS induce adverse efffects on tissues through oxidative damage of key biological structures. • On the other hand, CS-induced activation of inflammatory cells will further contribute to enhanced oxidant production.
  5. 5. ng oxidative and nitrosative stress induced by CS and air polutio ng oxidative and nitrosative stress induced by CS and air poluti Cigarette smoke + Air polution ↑ ROS ↑ Cytokines ↑NO (O2-) (nitric oxide) s dase eroxi op myel ONOO-(peroxynitrite) (peroxynitrite) OXIDATIVE STRESS OXIDATIVE STRESS NITROSATIVE STRESS NITROSATIVE STRESS Deleterious effects on tissues Deleterious effects on tissues
  6. 6. CS-INDUCED OXIDATIVE STRESS CS-INDUCED OXIDATIVE STRESS Lipid peroxidation markers Lipid peroxidation markers Morrow et al. N Eng J Med 1995
  7. 7. CS-INDUCED OXIDATIVE STRESS CS-INDUCED OXIDATIVE STRESS Rats exposed to CS for 30 days Park et al. Free Radic Biol Med 1998
  8. 8. CS-INDUCED OXIDATIVE STRESS CS-INDUCED OXIDATIVE STRESS Guinea pigs Guinea pigs Acute CS exposure Acute CS exposure 7 cigarettes 7 cigarettes Ardite et al. Respir Med 2006
  9. 9. Cigarette smoke & muscle Cigarette smoke & muscle structure structure Montes de Oca et al. Chest 2008
  10. 10. Cigarette smoke & muscle Cigarette smoke & muscle function function Wüst et al. Eur J Appl Physiol 2008
  11. 11. Cigarette smoke & body weight Cigarette smoke & body weight Ardite et al. Respir Med 2006
  12. 12. Cigarette smoke & body weight Cigarette smoke & body weight Barreiro et al. Am J Respir Crit Care Med 2010
  13. 13. COPD & BONES
  14. 14. Imbalance between osteoblast & osteoclast activity
  15. 15. Prevalence of osteoporosis in COPD
  16. 16. Risk factors of osteoporosis in COPD
  17. 17. Clinical guidance to treat osteoporosis in COPD
  18. 18. Routine chest CT Measured using DEXA
  19. 19. Changes in BMD, lung function, … & exacerbations
  20. 20. Annual change in thoracic vertebral BMD & exacerbations
  21. 21. COPD & MUSCLES
  22. 22. EVIDENCE OF MUSCLE DYSFUNCTION EVIDENCE OF MUSCLE DYSFUNCTION Muscle dysfunction in COPD ↓ Force & ↓ Endurance ± Cachexia ± Cachexia Muscle loss Muscle loss Exercise tolerance Exercise % pred. 150 respiratory muscles limb muscles MIP HG 100 50 0 Gosselink et al. AJRCCM 1996; 153. 976-80 QoL MEP QUAD HEALTHY COPD
  23. 23. PREVALENCE OF QUADRICEPS PREVALENCE OF QUADRICEPS DYSFUNCTION IN COPD PATIENTS DYSFUNCTION IN COPD PATIENTS Seymour et al. Eur Respir J 2010; 36: 81-88
  24. 24. QUADRICEPS WEAKNESS & DISEASE QUADRICEPS WEAKNESS & DISEASE SEVERITY IN COPD PATIENTS SEVERITY IN COPD PATIENTS Quadriceps weakness exists in the absence of severe airflow obstruction! Seymour et al. Eur Respir J 2010; 36: 81-88
  25. 25. QUADRICEPS WEAKNESS PREDICTS QUADRICEPS WEAKNESS PREDICTS MORTALITY IN COPD PATIENTS MORTALITY IN COPD PATIENTS Midthigh muscle cross sectional area is a better predictor of mortality than BMI in COPD patients Marquis et al. AJRCCM 2002; 166: 809-813. QMVC is simple and provides prognostic information than other parameters (age, BMI, and FEV1) in COPD Swallow et al. Thorax 2007; 62: 115-120.
  26. 26. MUSCLE DYSFUNCTION IN COPD Activity & type of muscle!!! Hypoxia Hypercapnia Deconditioning Inflammation Epigenetics Oxidative stress Apoptosis Genetic susceptibility Drugs Malnutrition Proteolysis Cigarette smoking Comorbidities
  27. 27. MUSCLE MASS LOSS IMBALANCE BETWEEN PROTEIN SYNTHESIS & DEGRADATION Muscle proteins Synthesis Synthesis abolism Protein an pathways Signaling Degradation Degradation Signaling pathways Protein catabolism
  28. 28. Enhanced muscle proteolysis Diaphragm, stable COPD patients: Diaphragm, stable COPD patients: Ottenheijm et al. Am J Respir Crit Care Med 2006 Ottenheijm et al. Am J Respir Crit Care Med 2006 Testelmans et al. Eur Respir J 2010 Testelmans et al. Eur Respir J 2010 Vastus lateralis, stable COPD patients: Vastus lateralis, stable COPD patients: Doucet et al. Am J Respir Crit Care Med 2007 Doucet et al. Am J Respir Crit Care Med 2007 Plant et al. Am J Respir Cell Mol Biol 2010 Plant et al. Am J Respir Cell Mol Biol 2010 Fermoselle et al. Eur Respir J 2012, 40: 851-62 Fermoselle et al. Eur Respir J 2012, 40: 851-62
  29. 29. Enhanced muscle proteolysis Vastus lateralis, COPD patients during exacerbations: Vastus lateralis, COPD patients during exacerbations: Crul et al. Cell Physiol Biochem 2010 Crul et al. Cell Physiol Biochem 2010 Vastus lateralis, stable COPD patients: Vastus lateralis, stable COPD patients: Troosters et al. Am J Respir Crit Care Med 2010 Troosters et al. Am J Respir Crit Care Med 2010 Vogiatzis et al. Eur Respir J 2010 Vogiatzis et al. Eur Respir J 2010 After general training
  30. 30. A FEW RESULTS…
  31. 31. REACTIVE OXYGEN SPECIES 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 STRESS Greater levels of ROS production than those normally 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 changes Proteolysis Apoptosis
  32. 32. LIMB MUSCLES: VASTUS LATERALIS Open muscle biopsy technique
  33. 33. * 0.50 * Mn-superoxide dismutase (OD, a.u.) 0.75 *** ††† 0.75 0.50 0.25 n.s. 0 0.25 0 Controls Non-wasted Muscle-wasted COPD patients CuZn-superoxide dismutase (OD, a.u.) Reactive carbonyl groups (OD, a.u.) REDOX BALANCE IN QUADRICEPS 1.2 n.s. * 0.8 0.4 0 Controls Non-wasted Muscle-wasted COPD patients Fermoselle et al. Eur Respir J 2012, 40: 851-62
  34. 34. OXIDATIVE STRESS: CLINICAL IMPLICATIONS Muscle protein oxidation – Quadriceps muscle force r= -0.648 p=0.043 1.2 r= -0.664 p=0.026 1.2 Reactive carbonyl groups, nmol/mg Reactive carbonyl groups, nmol/mg 1.1 1.0 .9 .8 .7 .6 1.0 .8 .6 .5 10 20 30 QMVC, kg E. Barreiro et al. Thorax 2008; 63: 100-107 40 50 4 6 8 Q twitch, kg 10 12 14
  35. 35. OXIDATIVE STRESS: CLINICAL IMPLICATIONS Muscle protein oxidation – Exercise capacity r=-0.539 p=0.038 r=-0.643 p=0.010 100 80 80 VO2max, % pred WRmax, % pred 60 40 60 40 20 20 2 3 4 5 6 7 8 9 Total protein carbonylation/GAPDH immunoreactivity E. Barreiro et al. Thorax 2009; 64: 13-19 2 3 4 5 6 7 8 Total protein carbonylation/GAPDH immunoreactivity 9
  36. 36. OXIDATIVELY MODIFIED PROTEINS Vastus lateralis Phosphocreatine (PCr) + ADP + H + CO2 + H2O E. Barreiro et al. Am J Respir Cell Mol Biol 2005 AC CK ATP + creatine HCO3- + H+
  37. 37. Oxidatively modified proteins in Smokers & COPD Carbonylated Proteins: Controls, Smokers & COPD Carbonylated Proteins: Controls, Smokers & COPD Vastus lateralis 14 *** *** Reactive carbonyl groups (OD, a.u.) *** *** 12 10 *** 8 6 4 * ** 2 ** 0 C S COPD Enolase C S COPD Aldolase Barreiro et al. AJRCCM 2010; 182: 477-488. C S COPD GAPDH C S COPD Creatine kinase C * S COPD ATP synthase C S COPD Carbonic anhydrase-3 C S COPD Actin
  38. 38. MUSCLE FIBER ATROPHY Fermoselle et al. Eur Respir J 2012, 40: 851-62
  39. 39. MUSCLE FIBER ATROPHY Severe COPD & Cachexia Fermoselle et al. Eur Respir J 2012, 40: 851-62
  40. 40. SUPEROXIDE ANION WITHIN MYONUCLEI Controls Non-wasted COPD Muscle-wasted COPD %O2- in myonuclei 40 *** ** * 20 Fermoselle et al. Eur Respir J 2012, 40: 851-62 0 Controls Non-wasted Muscle-wasted COPD patients
  41. 41. n.s. * 0.8 0.6 Ubiquitin-conjugating E214k (OD, a.u.) 1 0.4 * * p=0.08 * n.s. n.s. 0.2 0 0.2 0 0.3 n.s. n.s. 0.2 0.1 0 Controls Non-wasted Muscle-wasted COPD patients Fermoselle et al. Eur Respir J 2012, 40: 851-62 Ubiquitin ligase atrogin-1 (OD, a.u.) 0.4 Ubiquitin ligase MURF-1 (OD, a.u.) 20S proteasome subunit C8 (OD, a.u.) Total ubiquitinated proteins (OD, a.u.) Proteolysis: Ubiquitin-proteasome system 0.6 0.4 0.2 0 1.5 1 0.5 0 Controls Non-wasted Muscle-wasted COPD patients
  42. 42. MYOSIN CONTENT & OXIDATION MyHC content (OD, a.u.) 0.3 n.s. MyHC content 0.2 * † 0.1 0 Carbonylated MyHC (OD, a.u.) 0.1 * MyHC oxidation ** 0.05 0 Controls Non-wasted Muscle-wasted COPD patients Fermoselle et al. Eur Respir J 2012, 40: 851-62
  43. 43. HUMAN DIAPHRAGM Thoracotomy Thoracotomy
  44. 44. OXIDATIVE STRESS 1.5 * ns 1.0 0.5 0 CONTROLS MODERATE COPD Barreiro et al. Am J Respir Crit Care Med 2005 SEVERE COPD Total Carbonyl group formation (OD, a.u.) Total Carbonyl group formation (OD, a.u.) Oxidized proteins - Diaphragms 1.6 r = - 0.734 p < 0.01 1.2 0.8 0.4 20 40 60 FEV1 (% pred.) 80
  45. 45. OXIDATIVELY MODIFIED PROTEINS Diaphragms MW (KDa) 98 64 Creatine kinase isoforms α-1 actin Creatine kinase isoforms α-1 actin Creatine kinase isoforms α-1 actin Creatine kinase isoforms α-1 actin 50 36 30 Carbonic anhydrase isorfoms Carbonic anhydrase isorfoms Carbonic anhydrase isorfoms Control Control Carbonic anhydrase isorfoms Moderate COPD Moderate COPD MW (KDa) 98 64 Creatine kinase isoforms α-1 actin Creatine kinase isoforms α-1 actin 50 Creatine kinase isoforms α-1 actin Creatine kinase isoforms α-1 actin 36 Carbonic anhydrase isorfoms Carbonic anhydrase isorfoms 30 3 pH 10 3 Severe COPD Marin-Corral et al. Eur Respir J 2009; 33: 1309-1319 pH Severe COPD Carbonic anhydrase isorfoms Carbonic anhydrase isorfoms 10 3 pH Severe COPD 10 3 pH Severe COPD 10
  46. 46. MyHC content & oxidation Diaphragms, stable COPD MW (KDa) MW (KDa) +ve 250 Myosin Heavy Chain 250 Controls Moderate COPD Severe COPD GAPDH 36 Controls Moderate COPD Severe COPD MyHC oxidation MyHC content *** 1 n.s. *** 0.5 0 Controls Moderate COPD Severe COPD MyHC content / GAPDH MyHC carbonylation / GAPDH GAPDH 36 *** 1.5 n.s. 1 0.5 0 Controls Marin-Corral et al. Eur Respir J 2009. *** Moderate COPD Severe COPD
  47. 47. INFLAMMATION CYTOKINES IL4/IL13 IL-1Ra TNF-α Il-1β IL8 IL12 IFN-γ TGFβ IL10 ANTI-INFLAMMATORY PROINFLAMMATORY
  48. 48. Cytokines in the vastus lateralis of severe COPD patients p=0.04 p=0.008 1.0 TNF-alpha R II, pg/mL 1.25 40 TNF-alpha, pg/mL 50 30 20 10 0.75 0.50 0.25 0 0 CTL E. Barreiro et al. Thorax 2008; 63: 100-107 COPD CTL COPD
  49. 49. Cellular inflammation Patients with COPD, Vastus lateralis Patients with COPD, Vastus lateralis leucocyte Barreiro et al. J Appl Physiol 2011; 111: 808-817 macrophage
  50. 50. Cellular inflammation Barreiro et al. J Appl Physiol 2011; 111: 808-817
  51. 51. SYSTEMIC INFLAMMATION Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94.
  52. 52. SYSTEMIC INFLAMMATION IN SMOKING SYSTEMIC INFLAMMATION IN SMOKING MICE MICE Blood TNF-alpha levels, (pg/ml) 500 p=0.002 450 400 350 300 250 200 Ctl Barreiro et al. Respir Physiol Neurobiol 2012. CS
  53. 53. EXERCISE: Muscles in COPD
  54. 54. Endurance Exercise Training Blood Protein tyrosine nitration After exercise training, 8 weeks p = 0.093 p = 0.079 p = 0.029 2.60 2.40 Blood Protein Nitration (nM) 2.20 2.00 1.80 1.60 1.40 1.20 1.00 Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94. Pre Controls Post Controls Pre COPD Post COPD
  55. 55. Endurance Exercise Training Muscle protein tyrosine nitration Vastus lateralis After exercise training, 8 weeks p = 0.021 1.2 p = 0.155 p = 0.061 Muscle Protein Nitration (O.D, a.u) 1.0 0.8 0.6 0.4 0.2 0.0 Rodriguez et al. Free Radic Biol Med 2012; 52: 88-94. Pre Post Controls Controls Pre COPD Post COPD
  56. 56. Chronic exposure to CS
  57. 57. GUINEA PIG EXPOSED TO CIGARETTE SMOKE Guinea pigs chronically exposed to CS Guinea pigs chronically exposed to CS EXPOSURE TIME Time 0 3 months 7 cig/day CS, n=7 Control, n=7 Diaphragm Diaphragm Gastrocnemius Gastrocnemius Lungs Barreiro et al. Am J Respir Crit Care Med 2010. 4 months 7 cig/day CS, n=7 Control, n=7 Diaphragm Diaphragm Gastrocnemius Gastrocnemius Lungs 6 months 7 cig/day CS, n=7 Control, n=7 Diaphragm Diaphragm Gastrocnemius Gastrocnemius Lungs
  58. 58. GUINEA PIG EXPOSED TO CIGARETTE SMOKE 10 Diaphragms, 6 months Reactive carbonyl groups (OD, a.u.) Reactive carbonyl groups (OD, a.u.) Diaphragms, 3 months ** 8 6 4 2 0 C S C S C S C S Aldolase Creatine kinase ATP synthase *** 12 10 C S Enolase 14 8 6 4 2 0 Actin C S Enolase C S C S Aldolase C S C S Creatine kinase ATP synthase Actin Gastrocnemius, 3 months 10 ** 8 6 ** 4 2 * ** * * 0 C S C S C S C S C S C S C S C S ATP Enolase AldolaseTriose GAPDH Creatine Actin Tropo kinase synthase myosin phosphate isomerase Barreiro et al. Am J Respir Crit Care Med 2010. Reactive carbonyl groups (OD, a.u.) Reactive carbonyl groups (OD, a.u.) Carbonylated Proteins Carbonylated Proteins Gastrocnemius, 6 months 20 *** 16 12 8 4 *** *** *** * * 0 C S C S C S C S C S C S C S C S Enolase Aldolase Triose ATP Actin Tropo GAPDH Creatine kinase synthase phosphate myosin isomerase
  59. 59. MICE EXPOSED TO CIGARETTE SMOKE Mice chronically exposed to CS Mice chronically exposed to CS EXPOSURE TIME Time 0 6 months Male AKR/J mice 2 cig/day CS, n=13 Control, n=9 Diaphragm Diaphragm Gastrocnemius Gastrocnemius Lungs Barreiro et al. Respir Physiol Neurobiol 2012.
  60. 60. MICE EXPOSED TO CIGARETTE SMOKE Reactive carbonyl groups (OD, a.u.) Protein Carbonylation Protein Carbonylation p=0.017 3.0 p=0.009 2.0 1.0 Ctl CS diaphragm Barreiro et al. Respir Physiol Neurobiol 2012. Ctl CS gastrocnemius
  61. 61. IDENTIFICATION OF OXIDIZED PROTEINS Barreiro et al. Respir Physiol Neurobiol 2012.
  62. 62. COPD muscle & bone dysfunction: Present & Future Targets Environment,Triggers, Signaling pathways Targets Apoptosis Epigenetics Proteolysis Autophagy Senescence Muscle & bone loss Locomotor dysfunction & fractures ⇒ ↓ QoL
  63. 63. Questions that still need to be addressed? Questions that still need to be addressed? To target patients at earlier stages of their disease To identify “common” molecular markers/mechanisms of muscle and bone loss and dysfunction To elucidate the specific contribution of disuse as opposed to myopathy (?) ⇒ animal models? To evaluate the specific role of oxygen metabolism & mitochondria, especially in muscles To explore the potential reversibility induced by exercise +/- nutritional support on muscle mass & bone density loss and dysfunction
  64. 64. How can we try to answer all these questions? Large-scale clinical studies conducted on COPD patients & healthy controls Translational Research * Specimens from patients * Animal models * In vitro studies Molecular & Cellular analyses from different compartments
  65. 65. ACKNOWLEDGMENTS
  66. 66. THANK YOU!
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