AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

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Information about AIRWAYS, BONES & MUSCLES: DISEASE OR DISUSE?

Published on February 20, 2014

Author: Grupomenarini

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Barcelona-Boston Lung Conference

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?

CIGARETTE SMOKE COPD AIRWAYS & LUNGS

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

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.

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

CS-INDUCED OXIDATIVE STRESS CS-INDUCED OXIDATIVE STRESS Lipid peroxidation markers Lipid peroxidation markers Morrow et al. N Eng J Med 1995

CS-INDUCED OXIDATIVE STRESS CS-INDUCED OXIDATIVE STRESS Rats exposed to CS for 30 days Park et al. Free Radic Biol Med 1998

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

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 ± 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

PREVALENCE OF QUADRICEPS PREVALENCE OF QUADRICEPS DYSFUNCTION IN COPD PATIENTS DYSFUNCTION IN COPD PATIENTS Seymour et al. Eur Respir J 2010; 36: 81-88

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

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.

MUSCLE DYSFUNCTION IN COPD Activity & type of muscle!!! Hypoxia Hypercapnia Deconditioning Inflammation Epigenetics Oxidative stress Apoptosis Genetic susceptibility Drugs Malnutrition Proteolysis Cigarette smoking Comorbidities

MUSCLE MASS LOSS IMBALANCE BETWEEN PROTEIN SYNTHESIS & DEGRADATION Muscle proteins Synthesis Synthesis abolism Protein an pathways Signaling Degradation Degradation Signaling pathways Protein catabolism

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

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

A FEW RESULTS…

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

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 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

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

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

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+

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

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 Fermoselle et al. Eur Respir J 2012, 40: 851-62 0 Controls Non-wasted Muscle-wasted COPD patients

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

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

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 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

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

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

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, 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

Cellular inflammation Patients with COPD, Vastus lateralis Patients with COPD, Vastus lateralis leucocyte Barreiro et al. J Appl Physiol 2011; 111: 808-817 macrophage

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=0.002 450 400 350 300 250 200 Ctl Barreiro et al. Respir Physiol Neurobiol 2012. CS

EXERCISE: Muscles in COPD

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

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

Chronic exposure to CS

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

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

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.

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

IDENTIFICATION OF OXIDIZED PROTEINS Barreiro et al. Respir Physiol Neurobiol 2012.

COPD muscle & bone dysfunction: Present & Future Targets Environment,Triggers, Signaling pathways Targets Apoptosis Epigenetics Proteolysis Autophagy Senescence Muscle & bone loss Locomotor dysfunction & fractures ⇒ ↓ QoL

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

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

ACKNOWLEDGMENTS

THANK YOU!

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