Skip to main content

Advertisement

Log in

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Inspiratory function is essential for alveolar ventilation and expulsive behaviors that promote airway clearance (e.g., coughing and sneezing). Current evidence demonstrates that inspiratory dysfunction occurs during healthy aging and is accentuated by chronic heart failure (CHF). This inspiratory dysfunction contributes to key aspects of CHF and aging cardiovascular and pulmonary pathophysiology including: (1) impaired airway clearance and predisposition to pneumonia; (2) inability to sustain ventilation during physical activity; (3) shallow breathing pattern that limits alveolar ventilation and gas exchange; and (4) sympathetic activation that causes cardiac arrhythmias and tissue vasoconstriction. The diaphragm is the primary inspiratory muscle; hence, its neuromuscular integrity is a main determinant of the adequacy of inspiratory function. Mechanistic work within animal and cellular models has revealed specific factors that may be responsible for diaphragm neuromuscular abnormalities in CHF and aging. These include phrenic nerve and neuromuscular junction alterations as well as intrinsic myocyte abnormalities, such as changes in the quantity and quality of contractile proteins, accelerated fiber atrophy, and shifts in fiber type distribution. CHF, aging, or CHF in the presence of aging disturbs the dynamics of circulating factors (e.g., cytokines and angiotensin II) and cell signaling involving sphingolipids, reactive oxygen species, and proteolytic pathways, thus leading to the previously listed abnormalities. Exercise-based rehabilitation combined with pharmacological therapies targeting the pathways reviewed herein hold promise to treat diaphragm abnormalities and inspiratory muscle dysfunction in CHF and aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Elliott JE, Greising SM, Mantilla CB, Sieck GC (2015) Functional impact of sarcopenia in respiratory muscles. Respir Physiol Neurobiol. doi:10.1016/j.resp.2015.10.001

    PubMed  PubMed Central  Google Scholar 

  2. Mantilla CB, Seven YB, Zhan WZ, Sieck GC (2010) Diaphragm motor unit recruitment in rats. Respir Physiol Neurobiol 173(1):101–106. doi:10.1016/j.resp.2010.07.001

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mantilla CB, Sieck GC (2011) Phrenic motor unit recruitment during ventilatory and non-ventilatory behaviors. Respir Physiol Neurobiol 179(1):57–63. doi:10.1016/j.resp.2011.06.028

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sieck GC, Ferreira LF, Reid MB, Mantilla CB (2013) Mechanical properties of respiratory muscles. Compr Physiol 3(4):1553–1567. doi:10.1002/cphy.c130003

    PubMed  PubMed Central  Google Scholar 

  5. Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ (2013) Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol 305(5):R464–R477. doi:10.1152/ajpregu.00231.2013

    Article  CAS  PubMed  Google Scholar 

  6. Callahan LA, Supinski GS (2009) Sepsis-induced myopathy. Crit Care Med 37(10 Suppl):S354–S367. doi:10.1097/CCM.0b013e3181b6e439

    Article  PubMed  PubMed Central  Google Scholar 

  7. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB (2008) Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 358(13):1327–1335. doi:10.1056/NEJMoa070447

    Article  CAS  PubMed  Google Scholar 

  8. Hooijman PE, Beishuizen A, Witt CC, de Waard MC, Girbes AR, Spoelstra-de Man AM, Niessen HW, Manders E, van Hees HW, van den Brom CE, Silderhuis V, Lawlor MW, Labeit S, Stienen GJ, Hartemink KJ, Paul MA, Heunks LM, Ottenheijm CA (2015) Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients. Am J Respir Crit Care Med 191(10):1126–1138. doi:10.1164/rccm.201412-2214OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lindsay DC, Lovegrove CA, Dunn MJ, Bennett JG, Pepper JR, Yacoub MH, Poole-Wilson PA (1996) Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure. Eur Heart J 17(8):1239–1250

    Article  CAS  PubMed  Google Scholar 

  10. Hammond MD, Bauer KA, Sharp JT, Rocha RD (1990) Respiratory muscle strength in congestive heart failure. Chest 98(5):1091–1094

    Article  CAS  PubMed  Google Scholar 

  11. Hwee DT, Kennedy AR, Hartman JJ, Ryans J, Durham N, Malik FI, Jasper JR (2015) The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure. J Pharmacol Exp Ther 353(1):159–168. doi:10.1124/jpet.114.222224

    Article  CAS  PubMed  Google Scholar 

  12. Stassijns G, Lysens R, Decramer M (1996) Peripheral and respiratory muscles in chronic heart failure. Eur Respir J 9(10):2161–2167

    Article  CAS  PubMed  Google Scholar 

  13. Howell S, Maarek JM, Fournier M, Sullivan K, Zhan WZ, Sieck GC (1995) Congestive heart failure: differential adaptation of the diaphragm and latissimus dorsi. J Appl Physiol 79(2):389–397

    CAS  PubMed  Google Scholar 

  14. Greising SM, Mantilla CB, Gorman BA, Ermilov LG, Sieck GC (2013) Diaphragm muscle sarcopenia in aging mice. Exp Gerontol 48(9):881–887. doi:10.1016/j.exger.2013.06.001

    Article  PubMed  PubMed Central  Google Scholar 

  15. Greising SM, Mantilla CB, Medina-Martinez JS, Stowe JM, Sieck GC (2015) Functional impact of diaphragm muscle sarcopenia in both male and female mice. Am J Physiol Lung Cell Mol Physiol 309(1):L46–L52. doi:10.1152/ajplung.00064.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cacciani N, Ogilvie H, Larsson L (2014) Age related differences in diaphragm muscle fiber response to mid/long term controlled mechanical ventilation. Exp Gerontol 59:28–33. doi:10.1016/j.exger.2014.06.017

    Article  PubMed  Google Scholar 

  17. ATS/ERS (2002) Statement on respiratory muscle testing. Am J Respir Crit Care Med 166(4):518–624

    Article  Google Scholar 

  18. Janssens JP (2005) Aging of the respiratory system: impact on pulmonary function tests and adaptation to exertion. Clin Chest Med 26 (3):469–484, vi–vii. doi:10.1016/j.ccm.2005.05.004

  19. Black LF, Hyatt RE (1969) Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 99(5):696–702

    CAS  PubMed  Google Scholar 

  20. Neder JA, Andreoni S, Lerario MC, Nery LE (1999) Reference values for lung function tests. II. Maximal respiratory pressures and voluntary ventilation. Braz J Med Biol Res 32(6):719–727

    CAS  PubMed  Google Scholar 

  21. Enright PL, Adams AB, Boyle PJ, Sherrill DL (1995) Spirometry and maximal respiratory pressure references from healthy Minnesota 65- to 85-year-old women and men. Chest 108(3):663–669

    Article  CAS  PubMed  Google Scholar 

  22. Enright PL, Kronmal RA, Manolio TA, Schenker MB, Hyatt RE (1994) Respiratory muscle strength in the elderly correlates and reference values. Cardiovascular Health Study Research Group. Am J Respir Crit Care Med 149(2 Pt 1):430–438. doi:10.1164/ajrccm.149.2.8306041

    Article  CAS  PubMed  Google Scholar 

  23. Tolep K, Higgins N, Muza S, Criner G, Kelsen SG (1995) Comparison of diaphragm strength between healthy adult elderly and young men. Am J Respir Crit Care Med 152(2):677–682. doi:10.1164/ajrccm.152.2.7633725

    Article  CAS  PubMed  Google Scholar 

  24. Polkey MI, Harris ML, Hughes PD, Hamnegard CH, Lyons D, Green M, Moxham J (1997) The contractile properties of the elderly human diaphragm. Am J Respir Crit Care Med 155(5):1560–1564

    Article  CAS  PubMed  Google Scholar 

  25. Laghi F, Tobin MJ (2003) Disorders of the respiratory muscles. Am J Respir Crit Care Med 168(1):10–48. doi:10.1164/rccm.2206020

    Article  PubMed  Google Scholar 

  26. Coirault C, Hagege A, Chemla D, Fratacci MD, Guerot C, Lecarpentier Y (2001) Angiotensin-converting enzyme inhibitor therapy improves respiratory muscle strength in patients with heart failure. Chest 119(6):1755–1760

    Article  CAS  PubMed  Google Scholar 

  27. McParland C, Krishnan B, Wang Y, Gallagher CG (1992) Inspiratory muscle weakness and dyspnea in chronic heart failure. Am Rev Respir Dis 146(2):467–472

    Article  CAS  PubMed  Google Scholar 

  28. Carmo MM, Barbara C, Ferreira T, Branco J, Ferreira S, Rendas AB (2001) Diaphragmatic function in patients with chronic left ventricular failure. Pathophysiology 8(1):55–60

    Article  PubMed  Google Scholar 

  29. Evans SA, Watson L, Hawkins M, Cowley AJ, Johnston ID, Kinnear WJ (1995) Respiratory muscle strength in chronic heart failure. Thorax 50(6):625–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Witt C, Borges AC, Haake H, Reindl I, Kleber FX, Baumann G (1997) Respiratory muscle weakness and normal ventilatory drive in dilative cardiomyopathy. Eur Heart J 18(8):1322–1328

    Article  CAS  PubMed  Google Scholar 

  31. Ambrosino N, Opasich C, Crotti P, Cobelli F, Tavazzi L, Rampulla C (1994) Breathing pattern, ventilatory drive and respiratory muscle strength in patients with chronic heart failure. Eur Respir J 7(1):17–22

    Article  CAS  PubMed  Google Scholar 

  32. Filusch A, Ewert R, Altesellmeier M, Zugck C, Hetzer R, Borst MM, Katus HA, Meyer FJ (2011) Respiratory muscle dysfunction in congestive heart failure–the role of pulmonary hypertension. Int J Cardiol 150(2):182–185. doi:10.1016/j.ijcard.2010.04.006

    Article  PubMed  Google Scholar 

  33. Hughes PD, Polkey MI, Harrus ML, Coats AJ, Moxham J, Green M (1999) Diaphragm strength in chronic heart failure. Am J Respir Crit Care Med 160(2):529–534

    Article  CAS  PubMed  Google Scholar 

  34. Daganou M, Dimopoulou I, Alivizatos PA, Tzelepis GE (1999) Pulmonary function and respiratory muscle strength in chronic heart failure: comparison between ischaemic and idiopathic dilated cardiomyopathy. Heart 81(6):618–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dall’ago P, Chiappa GR, Guths H, Stein R, Ribeiro JP (2006) Inspiratory muscle training in patients with heart failure and inspiratory muscle weakness: a randomized trial. J Am Coll Cardiol 47(4):757–763

    Article  PubMed  Google Scholar 

  36. Ribeiro JP, Chiappa GR, Neder JA, Frankenstein L (2009) Respiratory muscle function and exercise intolerance in heart failure. Curr Heart Fail Rep 6(2):95–101

    Article  PubMed  Google Scholar 

  37. Tager T, Schell M, Cebola R, Frohlich H, Dosch A, Franke J, Katus HA, Wians FH Jr, Frankenstein L (2015) Biological variation, reference change value (RCV) and minimal important difference (MID) of inspiratory muscle strength (PImax) in patients with stable chronic heart failure. Clin Res Cardiol 104(10):822–830. doi:10.1007/s00392-015-0850-3

    Article  PubMed  Google Scholar 

  38. Bosnak-Guclu M, Arikan H, Savci S, Inal-Ince D, Tulumen E, Aytemir K, Tokgozoglu L (2011) Effects of inspiratory muscle training in patients with heart failure. Respir Med 105(11):1671–1681. doi:10.1016/j.rmed.2011.05.001

    Article  PubMed  Google Scholar 

  39. Verissimo P, Casalaspo TJ, Goncalves LH, Yang AS, Eid RC, Timenetsky KT (2015) High prevalence of respiratory muscle weakness in hospitalized acute heart failure elderly patients. PLoS One 10(2):e0118218. doi:10.1371/journal.pone.0118218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Kasahara Y, Izawa KP, Watanabe S, Osada N, Omiya K (2015) The relation of respiratory muscle strength to disease severity and abnormal ventilation during exercise in chronic heart failure patients. Res Cardiovasc Med 4(4):e228944. doi:10.5812/cardiovascmed.28944

    Article  Google Scholar 

  41. Hart N, Kearney MT, Pride NB, Green M, Lofaso F, Shah AM, Moxham J, Polkey MI (2004) Inspiratory muscle load and capacity in chronic heart failure. Thorax 59(6):477–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mancini DM, LaManca JJ, Donchez LJ, Levine S, Henson DJ (1995) Diminished respiratory muscle endurance persists after cardiac transplantation. Am J Cardiol 75(5):418–421

    Article  CAS  PubMed  Google Scholar 

  43. Mancini DM (1995) Pulmonary factors limiting exercise capacity in patients with heart failure. Prog Cardiovasc Dis 37(6):347–370

    Article  CAS  PubMed  Google Scholar 

  44. Sieck GC, Fournier M (1989) Diaphragm motor unit recruitment during ventilatory and nonventilatory behaviors. J Appl Physiol (1985) 66(6):2539–2545

    CAS  Google Scholar 

  45. Mantilla CB, Sieck GC (2013) Impact of diaphragm muscle fiber atrophy on neuromotor control. Respir Physiol Neurobiol 189(2):411–418. doi:10.1016/j.resp.2013.06.025

    Article  PubMed  Google Scholar 

  46. Mancini DM, Henson D, LaManca J, Levine S (1992) Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 86(3):909–918

    Article  CAS  PubMed  Google Scholar 

  47. Manning HL, Schwartzstein RM (1995) Pathophysiology of dyspnea. N Engl J Med 333(23):1547–1553

    Article  CAS  PubMed  Google Scholar 

  48. Woods PR, Olson TP, Frantz RP, Johnson BD (2010) Causes of breathing inefficiency during exercise in heart failure. J Card Fail 16(10):835–842. doi:10.1016/j.cardfail.2010.05.003

    Article  PubMed  PubMed Central  Google Scholar 

  49. Clark AL, Chua TP, Coats AJ (1995) Anatomical dead space, ventilatory pattern, and exercise capacity in chronic heart failure. Br Heart J 74(4):377–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yokoyama H, Sato H, Hori M, Takeda H, Kamada T (1994) A characteristic change in ventilation mode during exertional dyspnea in patients with chronic heart failure. Chest 106(4):1007–1013

    Article  CAS  PubMed  Google Scholar 

  51. Ponikowski P, Francis DP, Piepoli MF, Davies LC, Chua TP, Davos CH, Florea V, Banasiak W, Poole-Wilson PA, Coats AJ, Anker SD (2001) Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation 103(7):967–972

    Article  CAS  PubMed  Google Scholar 

  52. Baekey DM, Molkov YI, Paton JF, Rybak IA, Dick TE (2010) Effect of baroreceptor stimulation on the respiratory pattern: insights into respiratory-sympathetic interactions. Respir Physiol Neurobiol 174(1–2):135–145. doi:10.1016/j.resp.2010.09.006

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dempsey JA, Romer L, Rodman J, Miller J, Smith C (2006) Consequences of exercise-induced respiratory muscle work. Respir Physiol Neurobiol 151(2–3):242–250. doi:10.1016/j.resp.2005.12.015

    Article  PubMed  Google Scholar 

  54. Hill JM (2000) Discharge of group IV phrenic afferent fibers increases during diaphragmatic fatigue. Brain Res 856(1–2):240–244

    Article  CAS  PubMed  Google Scholar 

  55. Del Rio R, Marcus NJ, Schultz HD (2013) Carotid chemoreceptor ablation improves survival in heart failure: rescuing autonomic control of cardiorespiratory function. J Am Coll Cardiol 62(25):2422–2430. doi:10.1016/j.jacc.2013.07.079

    Article  PubMed  Google Scholar 

  56. Miller JD, Smith CA, Hemauer SJ, Dempsey JA (2007) The effects of inspiratory intrathoracic pressure production on the cardiovascular response to submaximal exercise in health and chronic heart failure. Am J Physiol Heart Circ Physiol 292(1):H580–H592. doi:10.1152/ajpheart.00211.2006

    Article  CAS  PubMed  Google Scholar 

  57. Olson TP, Joyner MJ, Dietz NM, Eisenach JH, Curry TB, Johnson BD (2010) Effects of respiratory muscle work on blood flow distribution during exercise in heart failure. J Physiol 588(Pt 13):2487–2501. doi:10.1113/jphysiol.2009.186056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mancini D, Donchez L, Levine S (1997) Acute unloading of the work of breathing extends exercise duration in patients with heart failure. J Am Coll Cardiol 29(3):590–596

    Article  CAS  PubMed  Google Scholar 

  59. O’Donnell DE, D’Arsigny C, Raj S, Abdollah H, Webb KA (1999) Ventilatory assistance improves exercise endurance in stable congestive heart failure. Am J Respir Crit Care Med 160(6):1804–1811. doi:10.1164/ajrccm.160.6.9808134

    Article  PubMed  Google Scholar 

  60. Morimoto K, Suzuki M, Ishifuji T, Yaegashi M, Asoh N, Hamashige N, Abe M, Aoshima M, Ariyoshi K, Adult Pneumonia Study G-J (2015) The burden and etiology of community-onset pneumonia in the aging Japanese population: a multicenter prospective study. PLoS One 10(3):e0122247. doi:10.1371/journal.pone.0122247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Welte T, Torres A, Nathwani D (2012) Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 67(1):71–79. doi:10.1136/thx.2009.129502

    Article  CAS  PubMed  Google Scholar 

  62. Wroe PC, Finkelstein JA, Ray GT, Linder JA, Johnson KM, Rifas-Shiman S, Moore MR, Huang SS (2012) Aging population and future burden of pneumococcal pneumonia in the United States. J Infect Dis 205(10):1589–1592. doi:10.1093/infdis/jis240

    Article  PubMed  Google Scholar 

  63. Mor A, Thomsen RW, Ulrichsen SP, Sorensen HT (2013) Chronic heart failure and risk of hospitalization with pneumonia: a population-based study. Eur J Intern Med 24(4):349–353. doi:10.1016/j.ejim.2013.02.013

    Article  PubMed  Google Scholar 

  64. Jackson ML, Neuzil KM, Thompson WW, Shay DK, Yu O, Hanson CA, Jackson LA (2004) The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis 39(11):1642–1650. doi:10.1086/425615

    Article  PubMed  Google Scholar 

  65. Meyer FJ, Borst MM, Zugck C, Kirschke A, Schellberg D, Kubler W, Haass M (2001) Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance. Circulation 103(17):2153–2158

    Article  CAS  PubMed  Google Scholar 

  66. Torchio R, Gulotta C, Greco-Lucchina P, Perboni A, Montagna L, Guglielmo M, Milic-Emili J (2006) Closing capacity and gas exchange in chronic heart failure. Chest 129(5):1330–1336. doi:10.1378/chest.129.5.1330

    Article  PubMed  Google Scholar 

  67. Cross TJ, Sabapathy S, Beck KC, Morris NR, Johnson BD (2012) The resistive and elastic work of breathing during exercise in patients with chronic heart failure. Eur Respir J 39(6):1449–1457. doi:10.1183/09031936.00125011

    Article  PubMed  Google Scholar 

  68. Agostoni P, Pellegrino R, Conca C, Rodarte JR, Brusasco V (2002) Exercise hyperpnea in chronic heart failure: relationships to lung stiffness and expiratory flow limitation. J Appl Physiol (1985) 92(4):1409–1416. doi:10.1152/japplphysiol.00724.2001

    Article  Google Scholar 

  69. Prakash YS, Sieck GC (1998) Age-related remodeling of neuromuscular junctions on type-identified diaphragm fibers. Muscle Nerve 21(7):887–895

    Article  CAS  PubMed  Google Scholar 

  70. Cardasis CA, LaFontaine DM (1987) Aging rat neuromuscular junctions: a morphometric study of cholinesterase-stained whole mounts and ultrastructure. Muscle Nerve 10(3):200–213. doi:10.1002/mus.880100303

    Article  CAS  PubMed  Google Scholar 

  71. de Souza PA, de Souza RW, Soares LC, Piedade WP, Campos DH, Carvalho RF, Padovani CR, Okoshi K, Cicogna AC, Matheus SM, Dal-Pai-Silva M (2015) Aerobic training attenuates nicotinic acetylcholine receptor changes in the diaphragm muscle during heart failure. Histol Histopathol 30(7):801–811. doi:10.14670/HH-11-581

    PubMed  Google Scholar 

  72. Wu P, Chawla A, Spinner RJ, Yu C, Yaszemski MJ, Windebank AJ, Wang H (2014) Key changes in denervated muscles and their impact on regeneration and reinnervation. Neural Regen Res 9(20):1796–1809. doi:10.4103/1673-5374.143424

    Article  PubMed  PubMed Central  Google Scholar 

  73. Adams L, Carlson BM, Henderson L, Goldman D (1995) Adaptation of nicotinic acetylcholine receptor, myogenin, and MRF4 gene expression to long-term muscle denervation. J Cell Biol 131(5):1341–1349

    Article  CAS  PubMed  Google Scholar 

  74. van Hees HW, van der Heijden HF, Hafmans T, Ennen L, Heunks LM, Verheugt FW, Dekhuijzen PN (2008) Impaired isotonic contractility and structural abnormalities in the diaphragm of congestive heart failure rats. Int J Cardiol 128(3):326–335. doi:10.1016/j.ijcard.2007.06.080

    Article  PubMed  Google Scholar 

  75. van Hees HW, van der Heijden HF, Ottenheijm CA, Heunks LM, Pigmans CJ, Verheugt FW, Brouwer RM, Dekhuijzen PN (2007) Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats. Am J Physiol Heart Circ Physiol 293(1):H819–H828. doi:10.1152/ajpheart.00085.2007

    Article  PubMed  CAS  Google Scholar 

  76. Stassijns G, Gayan-Ramirez G, De Leyn P, de Bock V, Dom R, Lysens R, Decramer M (1999) Effects of dilated cardiomyopathy on the diaphragm in the Syrian hamster. Eur Respir J 13(2):391–397

    Article  CAS  PubMed  Google Scholar 

  77. Supinski G, DiMarco A, Dibner-Dunlap M (1994) Alterations in diaphragm strength and fatiguability in congestive heart failure. J Appl Physiol 76(6):2707–2713

    CAS  PubMed  Google Scholar 

  78. Lecarpentier Y, Chemla D, Blanc FX, Pourny JC, Joseph T, Riou B, Coirault C (1998) Mechanics, energetics, and crossbridge kinetics of rabbit diaphragm during congestive heart failure. FASEB J 12(11):981–989

    CAS  PubMed  Google Scholar 

  79. Coirault C, Langeron O, Lambert F, Blanc FX, Lerebours G, Claude N, Riou B, Chemla D, Lecarpentier Y (1999) Impaired skeletal muscle performance in the early stage of cardiac pressure overload in rabbits: beneficial effects of angiotensin-converting enzyme inhibition. J Pharmacol Exp Ther 291(1):70–75

    CAS  PubMed  Google Scholar 

  80. Criswell DS, Powers SK, Herb RA, Dodd SL (1997) Mechanism of specific force deficit in the senescent rat diaphragm. Respir Physiol 107(2):149–155

    Article  CAS  PubMed  Google Scholar 

  81. Gosselin LE, Johnson BD, Sieck GC (1994) Age-related changes in diaphragm muscle contractile properties and myosin heavy chain isoforms. Am J Respir Crit Care Med 150(1):174–178. doi:10.1164/ajrccm.150.1.8025746

    Article  CAS  PubMed  Google Scholar 

  82. Empinado HM, Deevska GM, Nikolova-Karakashian M, Yoo JK, Christou DD, Ferreira LF (2014) Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content. Eur J Heart Fail 16(5):519–525. doi:10.1002/ejhf.73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ahn B, Beharry AW, Frye GS, Judge AR, Ferreira LF (2015) NAD(P)H oxidase subunit p47phox is elevated, and p47phox knockout prevents diaphragm contractile dysfunction in heart failure. Am J Physiol Lung Cell Mol Physiol 309(5):L497–L505. doi:10.1152/ajplung.00176.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mills DE, Johnson MA, Barnett YA, Smith WH, Sharpe GR (2015) The effects of inspiratory muscle training in older adults. Med Sci Sports Exerc 47(4):691–697. doi:10.1249/MSS.0000000000000474

    Article  CAS  PubMed  Google Scholar 

  85. Romer LM, McConnell AK (2003) Specificity and reversibility of inspiratory muscle training. Med Sci Sports Exerc 35(2):237–244. doi:10.1249/01.MSS.0000048642.58419.1E

    Article  PubMed  Google Scholar 

  86. Coirault C, Guellich A, Barbry T, Samuel JL, Riou B, Lecarpentier Y (2007) Oxidative stress of myosin contributes to skeletal muscle dysfunction in rats with chronic heart failure. Am J Physiol Heart CircPhysiol 292(2):H1009–H1017

    Article  CAS  Google Scholar 

  87. Lynch GS, Rafael JA, Hinkle RT, Cole NM, Chamberlain JS, Faulkner JA (1997) Contractile properties of diaphragm muscle segments from old mdx and old transgenic mdx mice. Am J Physiol 272(6 Pt 1):C2063–C2068

    CAS  PubMed  Google Scholar 

  88. Powers SK, Criswell D, Herb RA, Demirel H, Dodd S (1996) Age-related increases in diaphragmatic maximal shortening velocity. J Appl Physiol (1985) 80(2):445–451

    CAS  Google Scholar 

  89. Zhang YL, Kelsen SG (1990) Effects of aging on diaphragm contractile function in golden hamsters. Am Rev Respir Dis 142(6 Pt 1):1396–1401. doi:10.1164/ajrccm/142.6_Pt_1.1396

    Article  CAS  PubMed  Google Scholar 

  90. Ferreira LF, McDonagh B, Kelley RC, Coblentz PD, Patel N (2016) Aging-induced impairments in diaphragm isotonic contractile properties and modifications of proteomic and sphingolipid profile. FASEB J 30(4):A111

    Google Scholar 

  91. Graber TG, Kim JH, Grange RW, McLoon LK, Thompson LV (2015) C57BL/6 life span study: age-related declines in muscle power production and contractile velocity. Age (Dordr) 37(3):9773. doi:10.1007/s11357-015-9773-1

    Article  CAS  Google Scholar 

  92. Brooks SV, Faulkner JA (1988) Contractile properties of skeletal muscles from young, adult and aged mice. J Physiol 404:71–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Andersson DC, Betzenhauser MJ, Reiken S, Meli AC, Umanskaya A, Xie W, Shiomi T, Zalk R, Lacampagne A, Marks AR (2011) Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab 14(2):196–207. doi:10.1016/j.cmet.2011.05.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wehrens XH, Lehnart SE, Reiken S, van der Nagel R, Morales R, Sun J, Cheng Z, Deng SX, de Windt LJ, Landry DW, Marks AR (2005) Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. Proc Natl Acad Sci USA 102(27):9607–9612. doi:10.1073/pnas.0500353102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C, Huang F, Gaburjakova M, Gaburjakova J, Rosemblit N, Warren MS, He KL, Yi GH, Wang J, Burkhoff D, Vassort G, Marks AR (2003) PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. J Cell Biol 160(6):919–928. doi:10.1083/jcb.200211012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rullman E, Andersson DC, Melin M, Reiken S, Mancini DM, Marks AR, Lund LH, Gustafsson T (2013) Modifications of skeletal muscle ryanodine receptor type 1 and exercise intolerance in heart failure. J Heart Lung Transplant 32(9):925–929. doi:10.1016/j.healun.2013.06.026

    Article  PubMed  PubMed Central  Google Scholar 

  97. Dominguez JF, Howell S (2003) Compartmental analysis of steady-state diaphragm Ca2+ kinetics in chronic congestive heart failure. Cell Calcium 33(3):163–174

    Article  CAS  PubMed  Google Scholar 

  98. MacFarlane NG, Darnley GM, Smith GL (2000) Cellular basis for contractile dysfunction in the diaphragm from a rabbit infarct model of heart failure. Am J Physiol Cell Physiol 278(4):C739–C746

    CAS  PubMed  Google Scholar 

  99. Peters DG, Mitchell HL, McCune SA, Park S, Williams JH, Kandarian SC (1997) Skeletal muscle sarcoplasmic reticulum Ca(2 +)-ATPase gene expression in congestive heart failure. Circ Res 81(5):703–710

    Article  CAS  PubMed  Google Scholar 

  100. van Hees HW, Li YP, Ottenheijm CA, Jin B, Pigmans CJ, Linkels M, Dekhuijzen PN, Heunks LM (2008) Proteasome inhibition improves diaphragm function in congestive heart failure rats. Am J Physiol Lung Cell Mol Physiol 294(6):L1260–L1268. doi:10.1152/ajplung.00035.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Gordon AM, Homsher E, Regnier M (2000) Regulation of contraction in striated muscle. Physiol Rev 80(2):853–924

    CAS  PubMed  Google Scholar 

  102. Perkins WJ, Han YS, Sieck GC (1997) Skeletal muscle force and actomyosin ATPase activity reduced by nitric oxide donor. J Appl Physiol 83(4):1326–1332

    CAS  PubMed  Google Scholar 

  103. Coirault C, Chemla D, Pourny JC, Lambert F, Lecarpentier Y (1997) Instantaneous force-velocity-length relationship in diaphragmatic sarcomere. J Appl Physiol 82(2):404–412

    CAS  PubMed  Google Scholar 

  104. van Hees HW, Ottenheijm CA, Granzier HL, Dekhuijzen PN, Heunks LM (2010) Heart failure decreases passive tension generation of rat diaphragm fibers. Int J Cardiol 141(3):275–283. doi:10.1016/j.ijcard.2008.12.042

    Article  PubMed  Google Scholar 

  105. Irving T, Wu Y, Bekyarova T, Farman GP, Fukuda N, Granzier H (2011) Thick-filament strain and interfilament spacing in passive muscle: effect of titin-based passive tension. Biophys J 100(6):1499–1508. doi:10.1016/j.bpj.2011.01.059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Udaka J, Ohmori S, Terui T, Ohtsuki I, Ishiwata S, Kurihara S, Fukuda N (2008) Disuse-induced preferential loss of the giant protein titin depresses muscle performance via abnormal sarcomeric organization. J Gen Physiol 131(1):33–41. doi:10.1085/jgp.200709888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Thompson LV (2011) Age-related decline in actomyosin structure and function. In: Lynch GS (ed) Sarcopenia—age related muscle wasting and weakness. Springer, New York, pp 75–111. doi:10.1007/978-90-481-9713-2_5

    Chapter  Google Scholar 

  108. Szentesi P, Bekedam MA, van Beek-Harmsen BJ, van der Laarse WJ, Zaremba R, Boonstra A, Visser FC, Stienen GJ (2005) Depression of force production and ATPase activity in different types of human skeletal muscle fibers from patients with chronic heart failure. J Appl Physiol 99(6):2189–2195

    Article  CAS  PubMed  Google Scholar 

  109. Eddinger TJ, Moss RL, Cassens RG (1985) Fiber number and type composition in extensor digitorum longus, soleus, and diaphragm muscles with aging in Fisher 344 rats. J Histochem Cytochem 33(10):1033–1041

    Article  CAS  PubMed  Google Scholar 

  110. De Sousa E, Veksler V, Bigard X, Mateo P, Serrurier B, Ventura-Clapier R (2001) Dual influence of disease and increased load on diaphragm muscle in heart failure. J Mol Cell Cardiol 33(4):699–710. doi:10.1006/jmcc.2000.1336

    Article  PubMed  CAS  Google Scholar 

  111. Lima AR, Martinez PF, Damatto RL, Cezar MD, Guizoni DM, Bonomo C, Oliveira SA Jr, Dal-Pai Silva M, Zornoff LA, Okoshi K, Okoshi MP (2014) Heart failure-induced diaphragm myopathy. Cell Physiol Biochem 34(2):333–345. doi:10.1159/000363003

    Article  CAS  PubMed  Google Scholar 

  112. Ferreira LF, Coblentz P, Ahn B, Patel N, Yoo JK (2015) Mitochondria-targeted antioxidant treatment prevents elevation in diaphragm mitochondrial reactive oxygen species and weakness in chronic heart failure. FASEB J 29(826):812

    Google Scholar 

  113. Toth MJ, Palmer BM, LeWinter MM (2006) Effect of heart failure on skeletal muscle myofibrillar protein content, isoform expression and calcium sensitivity. Int J Cardiol 107(2):211–219. doi:10.1016/j.ijcard.2005.03.024

    Article  PubMed  Google Scholar 

  114. Tikunov B, Levine S, Mancini D (1997) Chronic congestive heart failure elicits adaptations of endurance exercise in diaphragmatic muscle. Circulation 95(4):910–916

    Article  CAS  PubMed  Google Scholar 

  115. Kim JH, Torgerud WS, Mosser KH, Hirai H, Watanabe S, Asakura A, Thompson LV (2012) Myosin light chain 3f attenuates age-induced decline in contractile velocity in MHC type II single muscle fibers. Aging Cell 11(2):203–212. doi:10.1111/j.1474-9726.2011.00774.x

    Article  CAS  PubMed  Google Scholar 

  116. Gosselin LE, Betlach M, Vailas AC, Thomas DP (1992) Training-induced alterations in young and senescent rat diaphragm muscle. J Appl Physiol (1985) 72(4):1506–1511

    CAS  Google Scholar 

  117. Stassijns G, Gayan-Ramirez G, De Leyn P, Verhoeven G, Herijgers P, de Bock V, Dom R, Lysens R, Decramer M (1998) Systolic ventricular dysfunction causes selective diaphragm atrophy in rats. Am J Respir Crit Care Med 158(6):1963–1967

    Article  CAS  PubMed  Google Scholar 

  118. Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P (2006) Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 114(17):1829–1837. doi:10.1161/CIRCULATIONAHA.106.649426

    Article  CAS  PubMed  Google Scholar 

  119. Klawitter PF, Clanton TL (2004) Tension-time index, fatigue, and energetics in isolated rat diaphragm: a new experimental model. J Appl Physiol 96(1):89–95. doi:10.1152/japplphysiol.00237.2003

    Article  PubMed  Google Scholar 

  120. Ferreira LF, Moylan JS, Gilliam LA, Smith JD, Nikolova-Karakashian M, Reid MB (2010) Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue. Am J Physiol Cell Physiol 299(3):C552–C560. doi:10.1152/ajpcell.00065.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li X, Moody MR, Engel D, Walker S, Clubb FJ Jr, Sivasubramanian N, Mann DL, Reid MB (2000) Cardiac-specific overexpression of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation 102(14):1690–1696

    Article  CAS  PubMed  Google Scholar 

  122. Greising SM, Ermilov LG, Sieck GC, Mantilla CB (2015) Ageing and neurotrophic signalling effects on diaphragm neuromuscular function. J Physiol 593(2):431–440. doi:10.1113/jphysiol.2014.282244

    Article  CAS  PubMed  Google Scholar 

  123. Seow CY, Stephens NL (1988) Fatigue of mouse diaphragm muscle in isometric and isotonic contractions. J Appl Physiol (1985) 64(6):2388–2393

    CAS  Google Scholar 

  124. Zhan WZ, Watchko JF, Prakash YS, Sieck GC (1998) Isotonic contractile and fatigue properties of developing rat diaphragm muscle. J Appl Physiol (1985) 84(4):1260–1268

    CAS  Google Scholar 

  125. Conti S, Cassis P, Benigni A (2012) Aging and the renin-angiotensin system. Hypertension 60(4):878–883. doi:10.1161/HYPERTENSIONAHA.110.155895

    Article  CAS  PubMed  Google Scholar 

  126. Rezk BM, Yoshida T, Semprun-Prieto L, Higashi Y, Sukhanov S, Delafontaine P (2012) Angiotensin II infusion induces marked diaphragmatic skeletal muscle atrophy. PLoS One 7(1):e30276. doi:10.1371/journal.pone.0030276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Dikalov S (2011) Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 51(7):1289–1301. doi:10.1016/j.freeradbiomed.2011.06.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Semprun-Prieto LC, Sukhanov S, Yoshida T, Rezk BM, Gonzalez-Villalobos RA, Vaughn C, Michael Tabony A, Delafontaine P (2011) Angiotensin II induced catabolic effect and muscle atrophy are redox dependent. Biochem Biophys Res Commun 409(2):217–221. doi:10.1016/j.bbrc.2011.04.122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Reid MB, Moylan JS (2011) Beyond atrophy: redox mechanisms of muscle dysfunction in chronic inflammatory disease. J Physiol 589(Pt 9):2171–2179. doi:10.1113/jphysiol.2010.203356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kwon OS, Smuder AJ, Wiggs MP, Hall SE, Sollanek KJ, Morton AB, Talbert EE, Toklu HZ, Tumer N, Powers SK (2015) AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction. J Appl Physiol (1985) jap 00237–jap 02015. doi:10.1152/japplphysiol.00237.2015

  131. Chiappa GR, Roseguini BT, Vieira PJ, Alves CN, Tavares A, Winkelmann ER, Ferlin EL, Stein R, Ribeiro JP (2008) Inspiratory muscle training improves blood flow to resting and exercising limbs in patients with chronic heart failure. J Am Coll Cardiol 51(17):1663–1671. doi:10.1016/j.jacc.2007.12.045

    Article  PubMed  Google Scholar 

  132. de Cavanagh EM, Inserra F, Ferder L (2011) Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria? Cardiovasc Res 89(1):31–40. doi:10.1093/cvr/cvq285

    Article  PubMed  CAS  Google Scholar 

  133. Hardin BJ, Campbell KS, Smith JD, Arbogast S, Smith J, Moylan JS, Reid MB (2008) TNF-alpha acts via TNFR1 and muscle-derived oxidants to depress myofibrillar force in murine skeletal muscle. J Appl Physiol 104(3):694–699. doi:10.1152/japplphysiol.00898.2007

    Article  CAS  PubMed  Google Scholar 

  134. Stasko SA, Hardin BJ, Smith JD, Moylan JS, Reid MB (2013) TNF signals via neuronal-type nitric oxide synthase and reactive oxygen species to depress specific force of skeletal muscle. J Appl Physiol (1985) 114(11):1629–1636. doi:10.1152/japplphysiol.00871.2012

    Article  CAS  Google Scholar 

  135. Janssen SP, Gayan-Ramirez G, Van den Bergh A, Herijgers P, Maes K, Verbeken E, Decramer M (2005) Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 111(8):996–1005. doi:10.1161/01.CIR.0000156469.96135.0D

    Article  CAS  PubMed  Google Scholar 

  136. Mann DL (2015) Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res 116(7):1254–1268. doi:10.1161/CIRCRESAHA.116.302317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9(2):139–150. doi:10.1038/nrm2329

    Article  CAS  PubMed  Google Scholar 

  138. Marchesini N, Hannun YA (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 82(1):27–44. doi:10.1139/o03-091

    Article  CAS  PubMed  Google Scholar 

  139. Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG (2001) Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol Heart Circ Physiol 281(6):H2337–H2365

    CAS  PubMed  Google Scholar 

  140. Supinski GS, Alimov AP, Wang L, Song XH, Callahan LA (2015) Neutral sphingomyelinase 2 is required for cytokine-induced skeletal muscle calpain activation. Am J Physiol Lung Cell Mol Physiol 309(6):L614–L624. doi:10.1152/ajplung.00141.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Schwagerl PJ, Talbert EE, Nguyen LM, Powers SK, Ferreira LF (2011) Sphingomyelinase promotes atrophy in C2C12 myotubes. FASEB J 25:LB602

    Google Scholar 

  142. Ferreira LF, Moylan JS, Stasko S, Smith JD, Campbell KS, Reid MB (2012) Sphingomyelinase depresses force and calcium sensitivity of the contractile apparatus in mouse diaphragm muscle fibers. J Appl Physiol 112(9):1538–1545. doi:10.1152/japplphysiol.01269.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Loehr JA, Abo-Zahrah R, Pal R, Rodney GG (2014) Sphingomyelinase promotes oxidant production and skeletal muscle contractile dysfunction through activation of NADPH oxidase. Front Physiol 5:530. doi:10.3389/fphys.2014.00530

    PubMed  Google Scholar 

  144. Bost ER, Frye GS, Ahn B, Ferreira LF (2015) Diaphragm dysfunction caused by sphingomyelinase requires the p47(phox) subunit of NADPH oxidase. Respir Physiol Neurobiol 205:47–52. doi:10.1016/j.resp.2014.10.011

    Article  CAS  PubMed  Google Scholar 

  145. Powers SK, Ji LL, Kavazis AN, Jackson MJ (2011) Reactive oxygen species: impact on skeletal muscle. Compr Physiol 1(2):941–969. doi:10.1002/cphy.c100054

    PubMed  PubMed Central  Google Scholar 

  146. Ferreira LF, Reid MB (2008) Muscle-derived ROS and thiol regulation in muscle fatigue. J Appl Physiol 104(3):853–860

    Article  CAS  PubMed  Google Scholar 

  147. Belch JJ, Bridges AB, Scott N, Chopra M (1991) Oxygen free radicals and congestive heart failure. Br Heart J 65(5):245–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nishiyama Y, Ikeda H, Haramaki N, Yoshida N, Imaizumi T (1998) Oxidative stress is related to exercise intolerance in patients with heart failure. Am Heart J 135(1):115–120

    Article  CAS  PubMed  Google Scholar 

  149. Mangner N, Linke A, Oberbach A, Kullnick Y, Gielen S, Sandri M, Hoellriegel R, Matsumoto Y, Schuler G, Adams V (2013) Exercise training prevents TNF-alpha induced loss of force in the diaphragm of mice. PLoS One 8(1):e52274. doi:10.1371/journal.pone.0052274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Supinski GS, Callahan LA (2005) Diaphragmatic free radical generation increases in an animal model of heart failure. J Appl Physiol 99(3):1078–1084

    Article  PubMed  Google Scholar 

  151. Powers SK, Jackson MJ (2008) Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 88(4):1243–1276. doi:10.1152/physrev.00031.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sakellariou GK, Jackson MJ, Vasilaki A (2014) Redefining the major contributors to superoxide production in contracting skeletal muscle. The role of NAD(P)H oxidases. Free Radic Res 48(1):12–29. doi:10.3109/10715762.2013.830718

    Article  CAS  PubMed  Google Scholar 

  153. Lassegue B, San Martin A, Griendling KK (2012) Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110(10):1364–1390. doi:10.1161/CIRCRESAHA.111.243972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jackson SH, Gallin JI, Holland SM (1995) The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med 182(3):751–758

    Article  CAS  PubMed  Google Scholar 

  155. Daiber A (2010) Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta 1797(6–7):897–906. doi:10.1016/j.bbabio.2010.01.032

    Article  CAS  PubMed  Google Scholar 

  156. Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 94(3):909–950. doi:10.1152/physrev.00026.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hepple RT (2014) Mitochondrial involvement and impact in aging skeletal muscle. Front Aging Neurosci 6:211. doi:10.3389/fnagi.2014.00211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Torii K, Sugiyama S, Tanaka M, Takagi K, Hanaki Y, Iida K, Matsuyama M, Hirabayashi N, Uno Y, Ozawa T (1992) Aging-associated deletions of human diaphragmatic mitochondrial DNA. Am J Respir Cell Mol Biol 6(5):543–549. doi:10.1165/ajrcmb/6.5.543

    Article  CAS  PubMed  Google Scholar 

  159. Torii K, Sugiyama S, Takagi K, Satake T, Ozawa T (1992) Age-related decrease in respiratory muscle mitochondrial function in rats. Am J Respir Cell Mol Biol 6(1):88–92. doi:10.1165/ajrcmb/6.1.88

    Article  CAS  PubMed  Google Scholar 

  160. Umanskaya A, Santulli G, Xie W, Andersson DC, Reiken SR, Marks AR (2014) Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging. Proc Natl Acad Sci USA 111(42):15250–15255. doi:10.1073/pnas.1412754111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jackson MJ (2015) Redox regulation of muscle adaptations to contractile activity and aging. J Appl Physiol (1985) 119(3):163–171. doi:10.1152/japplphysiol.00760.2014

    Article  CAS  Google Scholar 

  162. Xu KY, Zweier JL, Becker LC (1997) Hydroxyl radical inhibits sarcoplasmic reticulum Ca(2+)-ATPase function by direct attack on the ATP binding site. Circ Res 80(1):76–81

    Article  CAS  PubMed  Google Scholar 

  163. Hamilton SL, Reid MB (2000) RyR1 modulation by oxidation and calmodulin. Antiox Redox Signal 2(1):41–45

    Article  CAS  Google Scholar 

  164. Fedorova M, Kuleva N, Hoffmann R (2009) Reversible and irreversible modifications of skeletal muscle proteins in a rat model of acute oxidative stress. Biochim Biophys Acta 1792(12):1185–1193. doi:10.1016/j.bbadis.2009.09.011

    Article  CAS  PubMed  Google Scholar 

  165. Prochniewicz E, Lowe DA, Spakowicz DJ, Higgins L, O’Conor K, Thompson LV, Ferrington DA, Thomas DD (2008) Functional, structural, and chemical changes in myosin associated with hydrogen peroxide treatment of skeletal muscle fibers. Am J Physiol Cell Physiol 294(2):C613–C626

    Article  CAS  PubMed  Google Scholar 

  166. Andrade FH, Reid MB, Allen DG, Westerblad H (1998) Effect of hydrogen peroxide and dithiothreitol on contractile function of single skeletal muscle fibres from the mouse. J Physiol 509(Pt 2):565–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Nethery D, Stofan D, Callahan L, DiMarco A, Supinski G (1999) Formation of reactive oxygen species by the contracting diaphragm is PLA(2) dependent. J Appl Physiol 87(2):792–800

    CAS  PubMed  Google Scholar 

  168. Callahan LA, She ZW, Nosek TM (2001) Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus. J Appl Physiol 90(1):45–54

    CAS  PubMed  Google Scholar 

  169. Ferreira LF, Gilliam LA, Reid MB (2009) L-2-oxothiazolidine-4-carboxylate reverses glutathione oxidation and delays fatigue of skeletal muscle in vitro. J Appl Physiol 107:211–216

    Article  CAS  PubMed  Google Scholar 

  170. Moopanar TR, Allen DG (2006) The activity-induced reduction of myofibrillar Ca2+ sensitivity in mouse skeletal muscle is reversed by dithiothreitol. J Physiol 571(Pt 1):191–200

    Article  CAS  PubMed  Google Scholar 

  171. Reid MB, Haack KE, Franchek KM, Valberg PA, Kobzik L, West MS (1992) Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro. J Appl Physiol 73(5):1797–1804

    CAS  PubMed  Google Scholar 

  172. Supinski G, Nethery D, Stofan D, DiMarco A (1997) Effect of free radical scavengers on diaphragmatic fatigue. Am J Respir Crit Care Med 155(2):622–629

    Article  CAS  PubMed  Google Scholar 

  173. Criswell DS, Shanely RA, Betters JJ, McKenzie MJ, Sellman JE, Van Gammeren DL, Powers SK (2003) Cumulative effects of aging and mechanical ventilation on in vitro diaphragm function. Chest 124(6):2302–2308

    Article  PubMed  Google Scholar 

  174. Smuder AJ, Kavazis AN, Hudson MB, Nelson WB, Powers SK (2010) Oxidation enhances myofibrillar protein degradation via calpain and caspase-3. Free Radic Biol Med 49(7):1152–1160. doi:10.1016/j.freeradbiomed.2010.06.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Chung HS, Wang SB, Venkatraman V, Murray CI, Van Eyk JE (2013) Cysteine oxidative posttranslational modifications: emerging regulation in the cardiovascular system. Circ Res 112(2):382–392. doi:10.1161/CIRCRESAHA.112.268680

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Williams DL Jr, Swenson CA (1982) Disulfide bridges in tropomyosin. Effect on ATPase activity of actomyosin. Eur J Biochem 127(3):495–499

    Article  CAS  PubMed  Google Scholar 

  177. Moylan JS, Reid MB (2007) Oxidative stress, chronic disease, and muscle wasting. Muscle Nerve 35(4):411–429. doi:10.1002/mus.20743

    Article  CAS  PubMed  Google Scholar 

  178. Nikolova-Karakashian MN, Reid MB (2011) Sphingolipid metabolism, oxidant signaling, and contractile function of skeletal muscle. Antioxid Redox Signal. doi:10.1089/ars.2011.3940

    PubMed  PubMed Central  Google Scholar 

  179. Kandarian SC, Jackman RW (2006) Intracellular signaling during skeletal muscle atrophy. Muscle Nerve 33(2):155–165. doi:10.1002/mus.20442

    Article  CAS  PubMed  Google Scholar 

  180. Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol Rev 83(3):731–801. doi:10.1152/physrev.00029.2002

    Article  CAS  PubMed  Google Scholar 

  181. Supinski GS, Wang W, Callahan LA (2009) Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness. J Appl Physiol 107(5):1389–1396. doi:10.1152/japplphysiol.00341.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Nelson WB, Smuder AJ, Hudson MB, Talbert EE, Powers SK (2012) Cross-talk between the calpain and caspase-3 proteolytic systems in the diaphragm during prolonged mechanical ventilation. Crit Care Med 40(6):1857–1863. doi:10.1097/CCM.0b013e318246bb5d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hirai DM, Musch TI, Poole DC (2015) Exercise training in chronic heart failure: improving skeletal muscle O2 transport and utilization. Am J Physiol Heart Circ Physiol 309(9):H1419–H1439. doi:10.1152/ajpheart.00469.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Gielen S, Laughlin MH, O’Conner C, Duncker DJ (2015) Exercise training in patients with heart disease: review of beneficial effects and clinical recommendations. Prog Cardiovasc Dis 57(4):347–355. doi:10.1016/j.pcad.2014.10.001

    Article  PubMed  Google Scholar 

  185. Adamopoulos S, Schmid JP, Dendale P, Poerschke D, Hansen D, Dritsas A, Kouloubinis A, Alders T, Gkouziouta A, Reyckers I, Vartela V, Plessas N, Doulaptsis C, Saner H, Laoutaris ID (2014) Combined aerobic/inspiratory muscle training vs. aerobic training in patients with chronic heart failure: The Vent-HeFT trial: a European prospective multicentre randomized trial. Eur J Heart Fail 16(5):574–582. doi:10.1002/ejhf.70

    Article  CAS  PubMed  Google Scholar 

  186. Bowen TS, Rolim NP, Fischer T, Baekkerud FH, Medeiros A, Werner S, Bronstad E, Rognmo O, Mangner N, Linke A, Schuler G, Silva GJ, Wisloff U, Adams V (2015) Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle. Eur J Heart Fail 17(3):263–272. doi:10.1002/ejhf.239

    Article  CAS  PubMed  Google Scholar 

  187. Powers SK, Criswell D, Lieu FK, Dodd S, Silverman H (1992) Exercise-induced cellular alterations in the diaphragm. Am J Physiol 263(5 Pt 2):R1093–R1098

    CAS  PubMed  Google Scholar 

  188. Powers SK, Criswell D, Lieu FK, Dodd S, Silverman H (1992) Diaphragmatic fiber type specific adaptation to endurance exercise. Respir Physiol 89(2):195–207

    Article  CAS  PubMed  Google Scholar 

  189. Cahalin LP, Arena R, Guazzi M, Myers J, Cipriano G, Chiappa G, Lavie CJ, Forman DE (2013) Inspiratory muscle training in heart disease and heart failure: a review of the literature with a focus on method of training and outcomes. Expert Rev Cardiovasc Ther 11(2):161–177. doi:10.1586/erc.12.191

    Article  CAS  PubMed  Google Scholar 

  190. Laoutaris ID, Adamopoulos S, Manginas A, Panagiotakos DB, Kallistratos MS, Doulaptsis C, Kouloubinis A, Voudris V, Pavlides G, Cokkinos DV, Dritsas A (2013) Benefits of combined aerobic/resistance/inspiratory training in patients with chronic heart failure. A complete exercise model? A prospective randomised study. Int J Cardiol 167(5):1967–1972. doi:10.1016/j.ijcard.2012.05.019

    Article  PubMed  Google Scholar 

  191. Winkelmann ER, Chiappa GR, Lima CO, Viecili PR, Stein R, Ribeiro JP (2009) Addition of inspiratory muscle training to aerobic training improves cardiorespiratory responses to exercise in patients with heart failure and inspiratory muscle weakness. Am Heart J 158 (5):768 e761–767. doi:10.1016/j.ahj.2009.09.005

  192. Marco E, Ramirez-Sarmiento AL, Coloma A, Sartor M, Comin-Colet J, Vila J, Enjuanes C, Bruguera J, Escalada F, Gea J, Orozco-Levi M (2013) High-intensity vs. sham inspiratory muscle training in patients with chronic heart failure: a prospective randomized trial. Eur J Heart Fail 15(8):892–901. doi:10.1093/eurjhf/hft035

    Article  PubMed  Google Scholar 

  193. Di Lisa F, De Tullio R, Salamino F, Barbato R, Melloni E, Siliprandi N, Schiaffino S, Pontremoli S (1995) Specific degradation of troponin T and I by mu-calpain and its modulation by substrate phosphorylation. Biochem J 308(Pt 1):57–61

    Article  PubMed  PubMed Central  Google Scholar 

  194. Jaenisch RB, Hentschke VS, Quagliotto E, Cavinato PR, Schmeing LA, Xavier LL, Dal Lago P (2011) Respiratory muscle training improves hemodynamics, autonomic function, baroreceptor sensitivity, and respiratory mechanics in rats with heart failure. J Appl Physiol (1985) 111(6):1664–1670. doi:10.1152/japplphysiol.01245.2010

    Article  Google Scholar 

  195. Montemezzo D, Fregonezi GA, Pereira DA, Britto RR, Reid WD (2014) Influence of inspiratory muscle weakness on inspiratory muscle training responses in chronic heart failure patients: a systematic review and meta-analysis. Arch Phys Med Rehabil 95(7):1398–1407. doi:10.1016/j.apmr.2014.02.022

    Article  PubMed  Google Scholar 

  196. Palau P, Dominguez E, Nunez E, Schmid JP, Vergara P, Ramon JM, Mascarell B, Sanchis J, Chorro FJ, Nunez J (2014) Effects of inspiratory muscle training in patients with heart failure with preserved ejection fraction. Eur J Prev Cardiol 21(12):1465–1473. doi:10.1177/2047487313498832

    Article  PubMed  Google Scholar 

  197. Darnley GM, Gray AC, McClure SJ, Neary P, Petrie M, McMurray JJ, MacFarlane NG (1999) Effects of resistive breathing on exercise capacity and diaphragm function in patients with ischaemic heart disease. Eur J Heart Fail 1(3):297–300

    Article  CAS  PubMed  Google Scholar 

  198. Hulzebos EH, Helders PJ, Favie NJ, De Bie RA, Brutel de la Riviere A, Van Meeteren NL (2006) Preoperative intensive inspiratory muscle training to prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a randomized clinical trial. JAMA 296(15):1851–1857. doi:10.1001/jama.296.15.1851

    Article  CAS  PubMed  Google Scholar 

  199. Souza H, Rocha T, Pessoa M, Rattes C, Brandao D, Fregonezi G, Campos S, Aliverti A, Dornelas A (2014) Effects of inspiratory muscle training in elderly women on respiratory muscle strength, diaphragm thickness and mobility. J Gerontol A Biol Sci Med Sci 69(12):1545–1553. doi:10.1093/gerona/glu182

    Article  PubMed  Google Scholar 

  200. Smith BK, Martin AD, Vandenborne K, Darragh BD, Davenport PW (2012) Chronic intrinsic transient tracheal occlusion elicits diaphragmatic muscle fiber remodeling in conscious rodents. PLoS One 7(11):e49264. doi:10.1371/journal.pone.0049264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Rollier H, Bisschop A, Gayan-Ramirez G, Gosselink R, Decramer M (1998) Low load inspiratory muscle training increases diaphragmatic fiber dimensions in rats. Am J Respir Crit Care Med 157(3 Pt 1):833–839. doi:10.1164/ajrccm.157.3.9512103

    Article  CAS  PubMed  Google Scholar 

  202. Bisschop A, Gayan-Ramirez G, Rollier H, Gosselink R, Dom R, de Bock V, Decramer M (1997) Intermittent inspiratory muscle training induces fiber hypertrophy in rat diaphragm. Am J Respir Crit Care Med 155(5):1583–1589. doi:10.1164/ajrccm.155.5.9154861

    Article  CAS  PubMed  Google Scholar 

  203. Keens TG, Chen V, Patel P, O’Brien P, Levison H, Ianuzzo CD (1978) Cellular adaptations of the ventilatory muscles to a chronic increased respiratory load. J Appl Physiol Respir Environ Exerc Physiol 44(6):905–908

    CAS  PubMed  Google Scholar 

  204. Akabas SR, Bazzy AR, DiMauro S, Haddad GG (1989) Metabolic and functional adaptation of the diaphragm to training with resistive loads. J Appl Physiol (1985) 66(2):529–535

    CAS  Google Scholar 

  205. van Hees HW, Andrade Acuna G, Linkels M, Dekhuijzen PN, Heunks LM (2011) Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure. Br J Pharmacol 162(3):566–573. doi:10.1111/j.1476-5381.2010.01048.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Silvetti S, Nieminen MS (2015) Repeated or intermittent levosimendan treatment in advanced heart failure: an updated meta-analysis. Int J Cardiol 202:138–143. doi:10.1016/j.ijcard.2015.08.188

    Article  PubMed  Google Scholar 

  207. Russell AJ, Hartman JJ, Hinken AC, Muci AR, Kawas R, Driscoll L, Godinez G, Lee KH, Marquez D, Browne WFT, Chen MM, Clarke D, Collibee SE, Garard M, Hansen R, Jia Z, Lu PP, Rodriguez H, Saikali KG, Schaletzky J, Vijayakumar V, Albertus DL, Claflin DR, Morgans DJ, Morgan BP, Malik FI (2012) Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 18(3):452–455. doi:10.1038/nm.2618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Hooijman PE, Beishuizen A, de Waard MC, de Man FS, Vermeijden JW, Steenvoorde P, Bouwman RA, Lommen W, van Hees HW, Heunks LM, Dickhoff C, van der Peet DL, Girbes AR, Jasper JR, Malik FI, Stienen GJ, Hartemink KJ, Paul MA, Ottenheijm CA (2014) Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator. Am J Respir Crit Care Med 189(7):863–865. doi:10.1164/rccm.201312-2260LE

    Article  PubMed  PubMed Central  Google Scholar 

  209. Nagy L, Kovacs A, Bodi B, Pasztor ET, Fulop GA, Toth A, Edes I, Papp Z (2015) The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat. Br J Pharmacol. doi:10.1111/bph.13235

    PubMed Central  Google Scholar 

  210. Valentova M, von Haehling S (2014) An overview of recent developments in the treatment of heart failure: update from the ESC Congress 2013. Expert Opin Investig Drugs 23(4):573–578. doi:10.1517/13543784.2014.881799

    Article  CAS  PubMed  Google Scholar 

  211. Li YP, Chen Y, Li AS, Reid MB (2003) Hydrogen peroxide stimulates ubiquitin-conjugating activity and expression of genes for specific E2 and E3 proteins in skeletal muscle myotubes. Am J Physiol Cell Physiol 285(4):C806–C812. doi:10.1152/ajpcell.00129.2003

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Our research in this area is supported by grants from National Heart, Lung, and Blood Institute (R00-HL098453, R01-HL130318) and the American Heart Association (13GRNT17160000) to L. Ferreira. We would like to thank Jeremey Clark and Christine Coombes (Office of Communications, College of Health and Human Performance, University of Florida) for their assistance in preparation of illustrations for this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leonardo F. Ferreira.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kelley, R.C., Ferreira, L.F. Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology. Heart Fail Rev 22, 191–207 (2017). https://doi.org/10.1007/s10741-016-9549-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-016-9549-4

Keywords

Navigation