Exercise in pulmonary diseases: good or bad? An inflammatory point of view

PVRI Member Authors: Djuro Kosanovic, Ralph T. Schermuly, Norbert Weissmann, Michael Seimetz

Prelude

A person’s capacity is arguably essential to their quality of life, as well as overall life expectancy. Sadly, all the above is quite limited for patients with (cardio-)pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), due to several factors. Airflow limitations, alterations in gas exchange and muscle atrophy are predominant phenomena. To improve these disorders, exercise training seems to be a suitable instrument. However, physical activity can be beneficial as well as harmful for the health - dependent on the intensity and duration. For example, acute physical activity can increase the risk for acute coronary syndrome (ACS) and sudden cardiac death. On the contrary, it is known that continuous exercise training leads to decrease of cardiovascular morbidity and mortality1-3. The following controversial discussion will summarize some further aspects that explain the good and bad effects of exercise training with focus on the role of the inflammatory response in this context. This article should animate experts in the field to comment this topic, either by agreeing or disagreeing with our conclusions/hypotheses. The readers are invited to present arguments either pro or contra exercise training for patients not only with COPD but also with other cardiopulmonary diseases.

Impairments in lung function and breathing represent only one aspect of the disability experienced by individuals with COPD. Secondary consequences like the systemic inflammatory status and skeletal muscle dysfunction are further key limitations in these patients4 . The systemic inflammation of COPD patients is indicated by dysregulation of both cellular and humoral immune parameters. Patients with stable COPD present a peripheral leucocytosis, enhanced expression of leucocyte activation markers, and neutrophils show an increased oxidative burst. Serum levels of acute phase proteins like C-reactive protein (CRP), and pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α are increased during stable COPD4,5.

 

Inflammation and muscle in COPD

 In the last years, intense discussion has centered on the contribution of the systemic low grade inflammation in the pathophysiology of COPD. A number of studies focused on the relationship between inflammatory cytokines and skeletal muscle atrophy/dysfunction, since muscle wasting has been identified as a predictor of physical function and increased mortality in obstructive lung diseases6 . Muscular atrophy is accompanied by structural changes of muscle fibers that include a decreased proportion of oxidative muscle fibers, a loss of mitochondrial density and significant fiber type IIX atrophy7,8. From a functional point of view these changes induce a loss of endurance and deficits in muscle strength9 .There are several other factors which crosslink the systemic inflammatory status and muscle tissue.

At first, it is suggested that COPD patients tend to be sedentary, which might lead to both muscle atrophy as well as the accumulation of visceral fat, resulting in the activation of an additional network of systemic inflammatory pathways10-12. It is known that the pro-inflammatory cytokines TNF-α and IL-6 can induce muscle wasting by activating key mediators in the ubiquitin-proteasome pathway13,14. TNF-α is also known to inhibit skeletal muscle regenerative pathways through the induction of oxidative stress, and via nuclear factor (NF)-κB-dependent inhibition of MyoD, the transcription factor essential for regeneration of muscle15,16.

Immunomodulatory effects of exercise Exercise training has repeatedly shown itself to be an effective part of COPD therapeutic regimes; improving aerobic performance, muscle function, dyspnea, fatigue, muscle weakness and quality of life17,18. Acute and regular physical exercises are also known to have immunomodulatory effects19. A single bout of concentrated exercise is followed by a pro- or anti-inflammatory response, depending on type and intensity.

Pro-inflammatory effects of exercise

 Inflammation in skeletal muscle can, amongst others, occur after muscle fiber damage due to physical force and strenuous exercise. This can trigger release of inflammatory cytokines such as TNF-α, IL-1 and IL-6 generated by immune cells and/or damaged muscle tissues. Contracting skeletal muscles, especially if associated with inflammation, produce free radicals, known as reactive oxygen/nitrogen species (ROS/RNS). In the past, these radicals were considered as exclusively harmful for the muscle because of oxidative damage within the fiber. Nowadays, it is clear that both ROS and RNS are essential for signaling events involved in muscle adaptation to exercise and the remodeling that occurs during periods of prolonged inactivity. There is an abundance of evidence that low to moderate levels of ROS influence metabolic pathways in muscles related to glucose transport, ATPase activity, calcium release, creatine kinase activity, mitochondrial biogenesis and muscle fiber differentiation. Inflammation caused by muscle disuse and misuse is sensed by redox-sensitive signaling pathways like NF-κB and mitogen activated protein kinases (MAPKs)20,21. It was shown that the activity of the MAPK signaling modules is partially dependent on the type, duration and intensity of the contractile stimulus. The main function of MAPK pathway in muscle is the modulation of growth, metabolism, differentiation, transcription, translation and remodeling21. While transient oxidative stress is necessary in inflamed muscles to exert an anti-septic function and activation of signal transduction, extended severe oxidative stress can disturb long-term muscle welfare20,21.

Anti-inflammatory effects of exercise

In contrast, moderate acute exercise or regular exercise training are followed by an anti-inflammatory cytokine cascade. Thereby, IL-6 is a predominant cytokine which is produced by contracting muscle fibers in response to muscular glycogen depletion22. IL-6 stimulates the appearance of other anti-inflammatory cytokines such as interleukin-1 receptor antagonist (IL-1ra) and interleukin-10 (IL-10) in the circulation and inhibits the production of TNF-α23.

Exercise and inflammation in COPD

 Interestingly, some studies demonstrated that the immune response to exercise differs in subjects with already increased baseline cytokine levels such as COPD patients24,25. In this context, an increase of inflammatory cytokines was observed even after moderate types of endurance exercise. Therefore, it is suggested that exercise regimes should be highly individualized and controlled according to the patient´s exercise capacity, activity and inflammation level. COPD patients are mostly completely deconditioned and therefore show a significant cytokine response even at low intensity exercise. Thus, activity programs need to start at very low intensities and progress slowly. Then patients might benefit from the anti-inflammatory properties of exercise training. Furthermore, the nutritional status and the carbohydrate ingestion prior to exercise have to be controlled because both affect the exercise-induced cytokine response22.

The question for interactive discussion

We would like to postulate the following questions to the scientific community worldwide: Does a change of the immunological profile after exercise in patients with COPD mediate the beneficial effects of exercise in COPD patients? Is it necessary to perform exercise training in an individual and low intensity fashion to prevent pro-inflammatory effects of exercise?

All experts and other persons interested in the field are welcome to express their views on this topic, in the next volume of PVRI Chronicle.

 

References

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 7. Gosker HR, Engelen MP, van Mameren H, van Dijk PJ, van der Vusse GJ, Wouters EF, and Schols AM. Muscle fiber type IIX atrophy is involved in the loss of fat-free mass in chronic obstructive pulmonary disease. The American journal of clinical nutrition. 2002;76(1):113-9.

8. Gosker HR, van Mameren H, van Dijk PJ, Engelen MP, van der Vusse GJ, Wouters EF, and Schols AM. Skeletal muscle fibre-type shifting and metabolic profile in patients with chronic obstructive pulmonary disease. Eur Respir J. 2002;19(4):617-25.

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 12. Pedersen BK. The diseasome of physical inactivity--and the role of myokines in muscle--fat cross talk. The Journal of physiology. 2009;587(Pt 23):5559-68.

13. Haddad F, Zaldivar F, Cooper DM, and Adams GR. IL-6-induced skeletal muscle atrophy. Journal of applied physiology. 2005;98(3):911-7.

14. Llovera M, Garcia-Martinez C, Agell N, Lopez-Soriano FJ, and Argiles JM. TNF can directly induce the expression of ubiquitin-dependent proteolytic system in rat soleus muscles. Biochem Biophys Res Commun. 1997;230(2):238- 41.

15. Langen RC, Schols AM, Kelders MC, Van Der Velden JL, Wouters EF, and Janssen-Heininger YM. Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways. American journal of physiology Cell physiology. 2002;283(3):C714-21.

16. Guttridge DC, Mayo MW, Madrid LV, Wang CY, and Baldwin AS, Jr. NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science. 2000;289(5488):2363-6.

17. Franssen FM, Broekhuizen R, Janssen PP, Wouters EF, and Schols AM. Effects of whole-body exercise training on body composition and functional capacity in normal-weight patients with COPD. Chest. 2004;125(6):2021-8.

 18. Jensen D, Amjadi K, Harris-McAllister V, Webb KA, and O’Donnell DE. Mechanisms of dyspnoea relief and improved exercise endurance after furosemide inhalation in COPD. Thorax. 2008;63(7):606-13.

19. Nieman DC. Current perspective on exercise immunology. Current sports medicine reports. 2003;2(5):239-42.

20. Ji LL. Antioxidant signaling in skeletal muscle: a brief review. Experimental gerontology. 2007;42(7):582-93.

21. Kramer HF, and Goodyear LJ. Exercise, MAPK, and NF-kappaB signaling in skeletal muscle. Journal of applied physiology. 2007;103(1):388-95.

22. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC, Fleshner M, Green C, Pedersen BK, Hoffman-Goetz L, et al. Position statement. Part one: Immune function and exercise. Exercise immunology review. 2011;17(6):63.

23. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, and Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17(8):884-6.

24. Tirakitsoontorn P, Nussbaum E, Moser C, Hill M, and Cooper DM. Fitness, acute exercise, and anabolic and catabolic mediators in cystic fibrosis. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1432-7.

25. Rabinovich RA, Figueras M, Ardite E, Carbo N, Troosters T, Filella X, Barbera JA, Fernandez-Checa JC, Argiles JM, and Roca J. Increased tumour necrosis factor-alpha plasma levels during moderate-intensity exercise in COPD patients. Eur Respir J. 2003;21(5):789-94. 

Topics

Exercise
Oxidative stress and Oxidants/Antioxidants and Free Radicals

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PVRI Chronicle Vol 1: Issue 2 cover image

December 2014

PVRI Chronicle Vol 1: Issue 2

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