Activation of Satellite Cells in the Intercostal Muscles of Patients With Chronic Obstructive Pulmonary Disease

Martínez-Llorens, Juana; Casadevall, Carme; Lloreta, Josep; Orozco-Levi, Mauricio; Barreiro, Esther; Broquetas, Joan; Gea, Joaquim

doi:10.1016/S1579-2129(08)60038-5

Article information

Abstract

Bibliography

Download PDF

Statistics

Objective

The respiratory muscles of patients with chronic obstructive pulmonary disease (COPD) display evidence of structural damage in parallel with signs of adaptation. We hypothesized that this can only be explained by the simultaneous activation of satellite cells. The aim of this study was to analyze the number and activation of those cells along with the expression of markers of microstructural damage that are frequently associated with regeneration.

Patients and methods

The study included 8 patients with severe COPD (mean [SD] forced expiratory volume in 1 second, 33% [9%] of predicted) and 7 control subjects in whom biopsies were performed of the external intercostal muscle. The samples were analyzed by light microscopy to assess muscle fiber phenotype, electron microscopy to identify satellite cells, and real-time polymerase chain reaction to analyze the expression of the following markers: insulin-like growth factor 1, mechano growth factor, and embryonic and perinatal myosin heavy chains (MHC) as markers of microstructural damage; Pax-7 and m-cadherin as markers of the presence and activation of satellite cells, respectively; and MHC-I, IIa, and IIx as determinants of muscle fiber phenotype.

Results

The patients had larger fibers than healthy subjects (54 [6] vs 42 [4] μm2; P < .01) with a similar or slightly increased proportion of satellite cells, as measured by ultrastructural analysis (4.3% [1%] vs 3.7% [3.5%]; P > .05) or expression of Pax-7 (5.5 [4.1] vs 1.6 [0.8] arbitrary units [AU]; P < .05). In addition, there was greater activation of satellite cells in the patients, as indicated by increased expression of m-cadherin (3.8 [2.1] vs 1.0 [1.2] AU; P=.05). This was associated with increased expression of markers of microstructural damage: insulin-like growth factor 1, 0.35 (0.34) vs 0.09 (0.08) AU (P < .05); mechano growth factor, 0.45 (0.55) vs 0.13 (0.17) AU (P=.05). CONCLUSIONS: The intercostal muscles of patients with severe COPD show indirect signs of microstructural damage accompanied by satellite cell activation. This suggests the presence of ongoing cycles of lesion and repair that could partially explain the maintenance of the structural properties of the muscle.

Key words:

COPD

Muscle dysfunction

Damage

Repair

Satellite cells

Objetivo

Los músculos respiratorios de los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) presentan lesiones estructurales, que coexisten con signos de adaptación. Nuestra hipótesis es que esto sólo puede explicarse si se produce simultáneamente la activación de sus células satélite. El propósito del presente trabajo ha sido valorar el número y la eventual activación de dichas células, así como la expresión de marcadores de microlesión estructural, ligados a la regeneración.

Pacientes y métodos

Se incluyó en el estudio a 8 pacientes con EPOC grave -media ± desviación estándar del volumen espiratorio forzado en el primer segundo: un 33 ± 9% del valor de referencia-y a 7 controles, a quienes se realizó una biopsia del músculo intercostal externo. La muestra se analizó mediante microscopia óptica (fenotipo fibrilar), electrónica (células satélite) y técnica de reacción en cadena de la polimerasa en tiempo real (marcadores de microlesión: factor de crecimiento similar a la insulina de tipo 1, factor de crecimiento mecánico e isoformas de cadenas pesadas de miosina [MyHC] embrionaria e isoformas de perinatal; de presencia y activación de células satélite: Pax-7 y m-caderina, respectivamente; y condicionantes del fenotipo fibrilar: MyHC-I, IIa y IIx).

Resultados

Los pacientes tuvieron unas fibras mayores que los sujetos sanos (54 ± 6 frente a 42 ± 4 |a, m2; p < 0,01), con una población de células satélite conservada o ligeramente incrementada (cuantificación ultraestructural: 4,3 ± 1% frente al 3,7 ± 3,5%, p no significativa; Pax-7: 5,5 ± 4,1 frente a 1,6 ± 0,8, unidades arbitrarias [ua], respectivamente, p < 0,05) y una mayor activación (m-caderina: 3,8 ± 2,1 frente a 1,0 ± 1,2 ua; p = 0,05). Esto se asociaba a valores aumentados de marcadores de microlesión (factor de crecimiento similar a la insulina de tipo 1: 0,35 ± 0,34 frente a 0,09 ± 0,08 ua, p < 0,05; factor de crecimiento mecánico: 0,45 ± 0,55 frente a 0,13 ± 0,17 ua, p = 0,05).

Conclusiones

Los músculos intercostales de pacientes con EPOC grave muestran signos indirectos de microlesión, acompañados de la activación de sus células satélite. Esto apunta a la presencia de ciclos continuados de lesión y reparación, lo que podría explicar parcialmente la conservación de sus propiedades estructurales.

Palabras clave:

EPOC

Disfunción muscular

Daño

Reparación

Células satélite

Full text is only aviable in PDF

References

[1]

Global Initiative for Chronic Obstructive Lung Disease. Estrategia global para diagnóstico, tratamiento y prevención de la enfermedad pulmonar obstructiva crónica. Reunión de trabajo NHLBI/WHO. Available from: www.goldcopd.com

[2]

BR Celli, W MacNee, members and committee.

Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.

Eur Respir J, 23 (2004), pp. 932-946

Medline

[3]

E Swallow, D Reyes, N Hopkinson, W Man, R Porcher, E Cetti, et al.

Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease.

Thorax, 62 (2007), pp. 115-120

http://dx.doi.org/10.1136/thx.2006.062026 | Medline

[4]

J Gea, M Orozco-Levi, E Barreiro, A Ferrer, J Broquetas.

Structural and functional changes in the skeletal muscles of COPD patients: the “compartments” theory.

Monaldi Arch Chest Dis, 56 (2001), pp. 214-224

Medline

[5]

S Levine, T Nguyen, LR Kaiser, NA Rubinstein, G Maislin, C Gregory, et al.

Human diaphragm remodeling associated with chronic obstructive pulmonary disease: clinical implications.

Am J Respir Crit Care Med, 168 (2003), pp. 706-713

http://dx.doi.org/10.1164/rccm.200209-1070OC | Medline

[6]

F Whittom, J Jobin, PM Simard, P LeBlanc, C Simard, S Bernard, et al.

Histochemical and morphological characteristics of the vastus lateralis muscle in COPD patients.

Med Sci Sports Exerc, 30 (1998), pp. 1467-1474

Medline

[7]

E Barreiro, B De la Puente, J Minguella, JM Corominas, S Serrano, SN Hussain, et al.

Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease.

Am J Respir Crit Care Med, 171 (2005), pp. 1116-1124

http://dx.doi.org/10.1164/rccm.200407-887OC | Medline

[8]

E Barreiro, J Gea, J Corominas, SN Hussain.

Nitric oxide synthases and protein oxidation in the quadriceps femoris of patients with chronic obstructive pulmonary disease.

Am J Respir Cell Mol Biol, 29 (2003), pp. 771-778

http://dx.doi.org/10.1165/rcmb.2003-0138OC | Medline

[9]

M Orozco-Levi, J Lloreta, J Minguella, S Serrano, JM Broquetas, J Gea.

Injury of the human diaphragm associated with exertion and chronic obstructive pulmonary disease.

Am J Respir Crit Care Med, 164 (2001), pp. 1734-1739

http://dx.doi.org/10.1164/ajrccm.164.9.2011150 | Medline

[10]

M Orozco-Levi, MD Ferrer, C Coronell, A Ramírez-Sarmiento, J Lloreta, E Barreiro, et al.

Evidence of sarcomere disruption and myofibrillar degeneration in the quadriceps muscle of stable COPD patients.

Eur Respir J, 22 (2003), pp. 552S

[11]

A Grassino, M Hayot, G Czaika.

Biología del daño y la reparación muscular.

Arch Bronconeumol, 36 (2000), pp. 344-350

Medline

[12]

WD Reid, NA Macgowan.

Respiratory muscle injury in animal models and humans.

Mol Cell Biochem, 179 (1998), pp. 63-80

Medline

[13]

S Mehiri, E Barreiro, M Hayot, M Voyer, A Comtois, A Grassino, et al.

Time-based gene expression programme following diaphragm injury in a rat model.

Eur Respir J, 25 (2005), pp. 422-430

http://dx.doi.org/10.1183/09031936.05.00047704 | Medline

[14]

RC Langen, AM Schols, MC Kelders, JL Van der Velden, EF Wouters, YM Janssen-Heininger.

Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation.

Am J Respir Cell Mol Biol, 35 (2006), pp. 689-696

http://dx.doi.org/10.1165/rcmb.2006-0103OC | Medline

[15]

J Roca, J Sanchis, A Agustí-Vidal, F Segarra, D Navajas, R Rodríguez-Roisin, et al.

Spirometric reference values from a Mediterranean population.

Bull Eur Physiopathol Respir, 22 (1986), pp. 217-224

Medline

[16]

J Roca, F Burgos, JA Barbera, J Sunyer, R Rodríguez-Roisin, S Castellsagues, et al.

Prediction equations for plethysmographic lung volumes.

Respir Med, 92 (1998), pp. 454-460

Medline

[17]

J Roca, R Rodríguez-Roisin, E Cobo, F Burgos, J Pérez, JL Clausen.

Single breath carbon monoxide diffusing capacity prediction from a Mediterranean population.

Am Rev Respir Dis, 141 (1990), pp. 1026-1032

http://dx.doi.org/10.1164/ajrccm/141.4_Pt_1.1026 | Medline

[18]

A Ramírez-Sarmiento, M Orozco-Levi, R Guell, E Barreiro, N Hernández, S Mota, M Sangenis, et al.

Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes.

Am J Respir Crit Care Med, 166 (2002), pp. 1491-1497

http://dx.doi.org/10.1164/rccm.200202-075OCArticle | Medline

[19]

P Morales, J Sanchis, PJ Cordero, JL Dies.

Presiones respiratorias estáticas en adultos. Valores de referencia para población caucásica mediterránea.

Arch Bronconeumol, 33 (1997), pp. 213-219

Medline

[20]

R Bischoff.

The satellite cell and muscle regeneration.

pp. 97-118

[21]

F Kadi, LE Thornell.

Concomitant increases in myonuclear and satellite cell content in femeal trapezius muscle following strength training.

Histochem Cell Biol, 113 (2000), pp. 99-103

Medline

[22]

C Casadevall, C Coronell, AL Ramírez-Sarmiento, J Martínez-Llorens, E Barreiro, M Orozco-Levi, et al.

Upregulation of proinflammatory cytokines in the intercostal muscles of COPD patients.

Eur Respir J, 30 (2007), pp. 1-7

http://dx.doi.org/10.1183/09031936.00055407Article | Medline

[23]

E Zhu, BJ Petrof, J Gea, N Comtois, AE Grassino.

Diaphragm muscle fiber injury after inspiratory resistive breathing.

Am J Respir Crit Care Med, 155 (1997), pp. 1110-1116

http://dx.doi.org/10.1164/ajrccm.155.3.9116995 | Medline

[24]

J Gea, Q Hamid, G Czaika, E Zhu, V Mohan-Ram, G Goldspink, et al.

Expression of myosin heavy-chain isoforms in the respiratory muscles following inspiratory resistive breathing.

Am J Respir Crit Care Med, 161 (2000), pp. 1274-1278

http://dx.doi.org/10.1164/ajrccm.161.4.99040103 | Medline

[25]

F Haddad, CE Pandorf, JM Giger, KM Baldwin.

Striated muscle plasticity: regulation of the myosin heavy chain genes.

Skeletal muscle plasticity in health and disease: from genes to whole muscle, pp. 55-89

[26]

E Cortes, LF Te Fong, M Hameed, S Harridge, A Maclean, SY Yang, et al.

Insulin-like growth factor-1 gene splice variants as markers of muscle damage in levator ani muscle after the first vaginal delivery.

Am J Obstet Gynecol, 193 (2005), pp. 64-70

http://dx.doi.org/10.1016/j.ajog.2004.12.088 | Medline

[27]

M Hill, G Goldspink.

Expression and splicing of the insulin-likegrowth factor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage.

J Physiol, 549 (2003), pp. 409-418

http://dx.doi.org/10.1113/jphysiol.2002.035832 | Medline

[28]

A Mauro.

Satellite cell of skeletal muscle fibers.

J Biophys Bio-chem Cytol, 9 (1961), pp. 493-498

[29]

P Seale, MA Rudnicki.

A new look at the origen, fuction and “stem cell” status of muscle satellite cells.

Dev Biol, 218 (2000), pp. 115-124

http://dx.doi.org/10.1006/dbio.1999.9565 | Medline

[30]

KC Darr, E Schultz.

Exercise-induced satellite cell activation in growthing and mature skeletal muscle.

J Appl Physiol, 63 (1987), pp. 1816-1821

Medline

[31]

E Schultz, BH Lipton.

Skeletal muscle satellite cells: changes in proliferation potential as a function of age.

Mech Ageing Dev, 20 (1982), pp. 377-383

Medline

[32]

M Hill, G Goldspink.

Muscle satellite (stem) celll activation during local tissue injury and repair.

J Anat, 203 (2003), pp. 89-99

Medline

[33]

J Gea.

Myosin gene expression in the respiratory muscles.

Eur Respir J, 10 (1997), pp. 2404-2410

Medline

[34]

ML Duiverman, LA Van Eykern, PW Vennik, GH Koeter, EJ Maarsingh, PJ Wijkstra.

Reproducibility and responsiveness of a noninvasive EMG technique of the respiratory muscles in COPD patients and in healthy subjects.

J Appl Physiol, 96 (2004), pp. 1723-1729

http://dx.doi.org/10.1152/japplphysiol.00914.2003 | Medline

[35]

A De Troyer, PA Kirkwood, TA Wilson.

Respiratory action of the intercostal muscles.

Physiol Rev, 85 (2005), pp. 717-756

http://dx.doi.org/10.1152/physrev.00007.2004 | Medline

[36]

TW Hawke, DJ Garry.

Myogenic satellite cells: physiology to molecular biology.

J Appl Physiol, 91 (2001), pp. 534-551

Medline

This study was supported by funds from the European Union (Fifth Framework Programme, reference QLRT-2000-00417), the Spanish Ministry of Science and Technology (National R+D Plan, reference SAF 2001-0426), the Spanish Ministry of Health (Red RESPIRA, reference RTIC C03/11, Health Research Fund, Carlos III Health Institute), the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and the Generalitat de Cataluña (2005SGR01060).

J. Martínez-Llorens was supported by institutional funding from SEPAR, the Catalan Society of Pulmonology (SOCAP), and the Municipal Institute for Medical Research (IMIM, grants for residents, 2002 and 2003).

Indexed in:

Follow us:

Subscribe:

Indexed in:

Follow us:

Subscribe:

Subscribe to our newsletter