Iepsen, Ulrik Winning

Pedersen, Bente Klarlund

English

Copenhagen University Research Information System

u n i ve r s i t y  o f  co pe n h ag e n  Development of Limb Muscle Dysfunction in Chronic Obstructive Pulmonary DiseaseSmoking, Inflammation, or Simply Disuse?Iepsen, Ulrik Winning; Pedersen, Bente KlarlundPublished in:American Journal of Respiratory Cell and Molecular BiologyDOI:10.1165/rcmb.2019-0319EDPublication date:2020Document versionPublisher's PDF, also known as Version of recordDocument license:CC BY-NC-NDCitation for published version (APA):Iepsen, U. W., & Pedersen, B. K. (2020). Development of Limb Muscle Dysfunction in Chronic ObstructivePulmonary Disease: Smoking, Inflammation, or Simply Disuse? American Journal of Respiratory Cell andMolecular Biology, 62(2), 134-135. https://doi.org/10.1165/rcmb.2019-0319EDDownload date: 09. okt.. 2020EDITORIALSDevelopment of Limb Muscle Dysfunction in Chronic ObstructivePulmonary Disease: Smoking, Inflammation, or Simply Disuse?Limb muscle dysfunction in patients with chronic obstructivepulmonary disease (COPD) represents a significant clinical problemand is characterized by both intra- and extramuscular abnormalities(1, 2). The predominant extramuscular change is muscle wasting,which predicts a poor prognosis (2). The intramuscular pathologymainly affects the quadriceps muscle. Strong evidence indicates thatpatients with COPD demonstrate a shift in muscle fiber compositionfrom type I (oxidative, slow-twitch fibers) to type II (glycolytic, fast-twitch fibers) when compared with healthy control subjects (3).Likewise, the muscle fiber cross-sectional area is smaller inindividuals with COPD (4). Muscle metabolism mirrors thestructural changes, and most studies have reported a low oxidativeenzyme capacity in the quadriceps muscle of patients with COPD(5). In contrast, although the respiratory muscles adapt to achieve amore oxidative, fatigue-resistant profile in COPD, force generation issubnormal and increased ventilatory work redistributes the bloodvolume from locomotor to respiratory muscles (1). The functionalconsequences of COPD-associated limb muscle pathophysiologyinclude impaired muscle strength and endurance, which leads to lowexercise performance and aggravation of dyspnea during dailyphysical activities. These physiological and clinical effects arehallmarks of COPD symptomatology.In this issue of the Journal, Chan and colleagues (pp. 217–230)report their findings from an animal model of cigarette smoke(CS)-induced COPD (6). They examined the impact of CSexposure on skeletal muscle regeneration after muscle injury (MI)in male BALB/c mice by comparing CS-exposed (1MI) withunexposed (1MI) mice. Two control groups of CS-exposed (2MI)and unexposed (2MI) mice were also included. After 8 weeks ofCS exposure, the mice showed limb muscle abnormalities similar tothose observed in patients with COPD. This included muscleatrophy and markedly reduced oxidative fiber type composition ofthe hindlimb compared with unexposed mice. At this time point,hindlimb MI was induced by injection of barium chloride, whichnormally induces a robust activation of muscle satellite cells.Muscle outcomes were evaluated over the next 3 weeks. Loss ofmuscle mass and oxidative fibers was sustained throughout theexperiment in CS-exposed mice (1MI and 2MI). During the firstweek after MI, muscle contractile force was also lower in CS-exposed mice (1MI) than in unexposed mice (1MI), but graduallyrecovered at 3 weeks follow-up (6). The notion that muscle forcemight be restored independently of muscle fiber composition ormass is indeed a novel concept and provides new insight into theregenerative potential of the most commonly used countermeasureto muscle dysfunction in COPD, namely, exercise training.Numerous studies have explored the effects of exercise training onmuscle dysfunction in patients with COPD (4, 7–9). In an attemptto optimize the muscular response, investigators have explored theeffects of resistance training, and although the intramuscularstructure may adapt differently to resistance training and endurancetraining, the positive effects of these regimens on breathlessness andexercise capacity are similar (8). Likewise, resistance trainingprovides no additional effects on muscle strength in individuals withCOPD (10). The results from Chan and colleagues indicate that theregenerative potential is higher for muscle strength than for oxidativefiber-type proportions or atrophy in patients with COPD. This couldexplain why the intramuscular abnormalities are only partiallyreversible after 8–12 weeks of pulmonary rehabilitation (4, 8).Moreover, CS exposure seemed to reduce the activation of satellitecells in response to MI (6), which brings into question the rationalefor using resistance training (which relies on activation of satellitecells to regenerate damaged myofibers) as a countermeasure tomuscle dysfunction in COPD.The etiology of limb muscle dysfunction in patients withCOPD has been debated, and one of the prevailing hypothesesis that a local inflammatory process drives the breakdown of themuscle. The driver of this process is low-grade inflammation inthe respiratory system, primarily caused by tobacco smoking, thatspills over into the blood and consequently into skeletal muscle.However, investigators have not been able to confirm a highlyproinflammatory environment in the quadriceps muscle of patientswith COPD (9, 11). In CS-exposed mice, Chan and colleaguesfound a universal proinflammatory response in the pulmonary,circulatory, and muscular systems after 8 weeks of CS exposure thatmay constitute the mechanistic basis for the observed muscleadaptations (6). Studies in humans suggest that smoking impairsthe muscle protein synthesis process and increases the expressionof genes associated with impaired muscle maintenance, indicatingthat smoking per se likely increases the risk of sarcopenia and thatmuscle dysfunction may take place before the development ofCOPD (12). Another explanation for COPD-induced muscledysfunction could simply be reduced physical activity. Becausephysical activity was not recorded by Chan and colleagues, we canonly speculate about whether smoking induced physical inactivityrelative to controls. In patients with COPD, the intramuscularcharacteristics deteriorate along with disease severity, and thus theproportion of type I fibers in the quadriceps muscle is inverselycorrelated with forced expiratory volume in 1 second (3). Hence, adecline in lung function might reduce physical activity and therebycontribute to the limb muscle deconditioning seen in COPD.Finally, local muscle hypoxia might explain the maladaptationof limb muscles in COPD. Local muscle oxygen availability isThis article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1165/rcmb.2019-0319ED on September 18, 2019134 American Journal of Respiratory Cell and Molecular Biology Volume 62 Number 2 | February 2020 determined by an integrated transport system comprised ofventilation, lung diffusion, muscle circulation, and muscle diffusion(13), all of which are impaired in COPD. Accordingly, musclecells may adapt anaerobically to maintain their function in alocal hypoxic environment. This seems plausible consideringthe characteristics of muscle dysfunction in COPD, including aglycolytic fiber type dominance, higher anaerobic metabolism,and lower oxidative enzyme activity as described above.Direct evidence of local muscle hypoxia as a driver of muscledysfunction in patients with COPD is limited. However, altitudestudies in healthy subjects have shown that long-term exposureto hypoxia results in loss of muscle mass and a reduction inmuscle fiber cross-sectional area. Likewise, muscle oxidativecapacity is reduced together with muscle contractile functionduring hypoxia (14, 15). Thus, the muscle abnormalities observedin patients with COPD and in CS-exposed mice (6) are likelyto develop in healthy individuals when they are exposed to chronichypoxia. nAuthor disclosures are available with the text of this article atwww.atsjournals.org.Ulrik Winning Iepsen, M.D., Ph.D.Bente Klarlund Pedersen, M.D., DMSc.Centre of Inflammation and MetabolismandCentre for Physical Activity ResearchUniversity of CopenhagenRigshospitalet, DenmarkORCID ID: 0000-0002-8140-2583 (U.W.I.).References1. Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare´ R,et al.; ATS/ERS Ad Hoc Committee on Limb Muscle Dysfunction inCOPD. An official American Thoracic Society/European RespiratorySociety statement: update on limb muscle dysfunction in chronicobstructive pulmonary disease. Am J Respir Crit Care Med 2014;189:e15–e62.2. Vestbo J, Prescott E, Almdal T, Dahl M, Nordestgaard BG, Andersen T,et al. Body mass, fat-free body mass, and prognosis in patients withchronic obstructive pulmonary disease from a random populationsample: findings from the Copenhagen City Heart Study. Am J RespirCrit Care Med 2006;173:79–83.3. Gosker HR, Zeegers MP, Wouters EF, Schols AM. Muscle fibre typeshifting in the vastus lateralis of patients with COPD is associated withdisease severity: a systematic review and meta-analysis. Thorax 2007;62:944–949.4. Gouzi F, Pre´faut C, Abdellaoui A, Roudier E, de Rigal P, Molinari N, et al.Blunted muscle angiogenic training-response in COPD patientsversus sedentary controls. Eur Respir J 2013;41:806–814.5. Maltais F, LeBlanc P, Whittom F, Simard C, Marquis K, Be´langer M, et al.Oxidative enzyme activities of the vastus lateralis muscle and thefunctional status in patients with COPD. Thorax 2000;55:848–853.6. Chan SMH, Cerni C, Passey S, Seow HJ, Bernardo I, van der Poel C,et al. Cigarette smoking exacerbates skeletal muscle injury withoutcompromising its regenerative capacity. Am J Respir Cell Mol Biol2020;62:217–230.7. Spruit MA, Gosselink R, Troosters T, De Paepe K, Decramer M.Resistance versus endurance training in patients with COPD andperipheral muscle weakness. Eur Respir J 2002;19:1072–1078.8. Iepsen UW, Munch GDW, Rugbjerg M, Rinnov AR, Zacho M, MortensenSP. Effect of endurance versus resistance training on quadricepsmuscle dysfunction in COPD: a pilot study. Int J Chron ObstructPulmon Dis 2016;11:2659–2669.9. Ryrsø CK, Thaning P, Siebenmann C, Lundby C, Lange P, Pedersen BK,et al. Effect of endurance versus resistance training on local muscleand systemic inflammation and oxidative stress in COPD. Scand JMed Sci Sports 2018;28:2339–2348.10. Iepsen UW, Jørgensen KJ, Ringbaek T, Hansen H, Skrubbeltrang C,Lange P. A systematic review of resistance training versus endurancetraining in COPD. J Cardiopulm Rehabil Prev 2015;35:163–172.11. Barreiro E, Schols AM, Polkey MI, Galdiz JB, Gosker HR, Swallow EB,et al.; ENIGMA in COPD project. Cytokine profile in quadricepsmuscles of patients with severe COPD. Thorax 2008;63:100–107.12. Petersen AM, Magkos F, Atherton P, Selby A, Smith K, Rennie MJ,et al. Smoking impairs muscle protein synthesis and increasesthe expression of myostatin and MAFbx in muscle. Am J PhysiolEndocrinol Metab 2007;293:E843–E848.13. Wagner PD. The physiological basis of pulmonary gas exchange:implications for clinical interpretation of arterial blood gases. EurRespir J 2015;45:227–243.14. MacDougall JD, Green HJ, Sutton JR, Coates G, Cymerman A, YoungP, et al. Operation Everest II: structural adaptations in skeletalmuscle in response to extreme simulated altitude. Acta PhysiolScand 1991;142:421–427.15. Green HJ, Sutton JR, Cymerman A, Young PM, Houston CS. OperationEverest II: adaptations in human skeletal muscle. J Appl Physiol(1985) 1989;66:2454–2461.EDITORIALSEditorials 135 

Development of Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease:Smoking, Inflammation, or Simply Disuse?

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Development of Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease:Smoking, Inflammation, or Simply Disuse?

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