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Henrot, P.; Dupin, I.; Schilfarth, P.; Esteves, P.; Blervaque, L.; Zysman, M.; Gouzi, F.; Hayot, M.; Pomiès, P.; Berger, P. Inflammation Leads to Skeletal Muscle Wasting in COPD. Encyclopedia. Available online: https://encyclopedia.pub/entry/48127 (accessed on 08 July 2024).
Henrot P, Dupin I, Schilfarth P, Esteves P, Blervaque L, Zysman M, et al. Inflammation Leads to Skeletal Muscle Wasting in COPD. Encyclopedia. Available at: https://encyclopedia.pub/entry/48127. Accessed July 08, 2024.
Henrot, Pauline, Isabelle Dupin, Pierre Schilfarth, Pauline Esteves, Léo Blervaque, Maéva Zysman, Fares Gouzi, Maurice Hayot, Pascal Pomiès, Patrick Berger. "Inflammation Leads to Skeletal Muscle Wasting in COPD" Encyclopedia, https://encyclopedia.pub/entry/48127 (accessed July 08, 2024).
Henrot, P., Dupin, I., Schilfarth, P., Esteves, P., Blervaque, L., Zysman, M., Gouzi, F., Hayot, M., Pomiès, P., & Berger, P. (2023, August 16). Inflammation Leads to Skeletal Muscle Wasting in COPD. In Encyclopedia. https://encyclopedia.pub/entry/48127
Henrot, Pauline, et al. "Inflammation Leads to Skeletal Muscle Wasting in COPD." Encyclopedia. Web. 16 August, 2023.
Inflammation Leads to Skeletal Muscle Wasting in COPD
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24076454

Inflammation is one of the primary drivers of skeletal muscle wasting in Chronic Obstructive Pulmonary Disease (COPD), through its catabolic effects.

cachexia interleukin metabolism

1. Tumor Necrosis Factor α (TNF-α)

Classically, circulating TNF-α is reported to be higher in COPD patients than controls and negatively correlated to lean mass [1][2], as well as to muscle strength, including upper muscles [3]. However, this correlation seems to be consistent only in cachectic patients [4]. Moreover, with regards to muscular TNF-α, significantly elevated, decreased, and unaltered levels have been reported in the quadriceps of COPD patients [5][6][7], or even undetected at the protein level [8][9], although the effects of TNF-α could also be mediated by the elevated circulating levels. Mechanistically, TNF-α plays a dual role in muscle mass regulation, possibly via differential signaling according to receptor binding (TNF-R1 or TNF-R2) [10][11]. On the catabolic counterpart, TNF-α promotes the inflammatory response by binding on TNF-R at the macrophage surface and activating the nuclear factor-kappa B (NF-кB) pathway via the inhibitory-kappa B kinase alpha (IKKα) activation, thus supporting the M1-biased (inflammatory) phenotype. TNF-α secreted by myeloid cells (CD68+ macrophages) inhibits myotubes fusion in vivo [12], supporting its catabolic role. In vitro, it can be induced in C2C12 myotubes by serum amyloid A, which is increased during COPD exacerbations [13]. Possibly in a paracrine/autocrine fashion, its secretion activates glycolytic metabolism in C2C12 myotubes in a NF-кB-dependent manner, as well as enhancing the secretion of HIF1α, a key transcription factor induced in hypoxic or inflammatory conditions [14]. In the same study, HIF1α and its downstream target vascular endothelial growth factor (VEGF) were found elevated in quadriceps biopsies of COPD patients and correlated to the level of muscular TNF-α. Finally, a recent study has found that the downregulation of histone deacetylase 2 (HDAC2) by RNA interference in cultured primary myotubes increased TNF-α production and cell apoptosis [15]. HDAC2 belongs to a family of enzymes which classically downregulate inflammatory genes’ expression. The authors also evidenced a decrease of HDAC2 level in the quadriceps of COPD patients, associated with an increase in the NF-кB pathway.
However, some in vivo models seem to counteract in vitro data. Indeed, a mice model of TNF-α-signaling knock out (TNF-R2 KO) exhibited a more severe phenotype of skeletal muscle wasting (including reduced fibers’ CSA and an increase of type IIx myofibers) than wild-type littermates [10] after cigarette smoke (CS) exposure. Other data support the anabolic effects of TNF-α, which acts as a mitogen for satellite cells [16]. In myocytes, the binding of TNF-α to its receptor TNF-R activates the p38-mitogen-activated protein kinase (MAPK) pathway, leading to a silencing of target genes such as Pax7 and Notch1 (via an epigenetic control), promoting satellite cell differentiation into myotubes [17], in contrast to that previously reported [18]. The latter study also showed an increase in mitochondrial content in IKKα-expressing myotubes. Other models tend to corroborate in vitro data, such as a mouse model exposed to CS and exhibiting increased circulating TNF-α levels, which were correlated to detrimental outcomes such as muscle mass, decreased capillarization, and increased catabolism [19]. Moreover, an overexpression of TNF-α in the lung leads to an increased muscle fatigue, decreased muscle mass and mitochondrial content, and increased catabolism (mostly in male mice) [20]. These data might suggest that part of the deleterious effects of inflammation are secondary. Of note, therapies against TNF-α have not proven to be effective for various outcomes such as dyspnea or a number of exacerbations [21], suggesting that this cytokine is not the primary or at least the sole driver of COPD inflammation.

2. Interleukin-6 (IL-6)

Circulating IL-6 is also classically elevated in COPD patients compared to healthy subjects, both during and outside exacerbations [22] and associated with reduced quadriceps strength [23]. Like TNF-α, IL-6 is considered as a “double-edged sword” with proinflammatory (catabolic) and anti-inflammatory (anabolic) effects (see the review in [24]) according to local immune cells and the cytokines’ microenvironment. Overall, the pilot study of Tsujinaka and colleagues showed that transgenic mice chronically overexpressing IL-6 exhibit a marked muscle atrophy [25]; however, the knockout of IL-6 was not sufficient to prevent sarcopenia in a sepsis mouse model [26]. In muscle from COPD patients, IL-6 has been reported as unchanged at the transcriptional level (at both stable and exacerbation states) compared to that of healthy controls [5][6].
In vitro, IL-6 bears anabolic effects by regulating satellite cells’ function and enhancing glucose metabolism; furthermore, a loss of IL-6 signaling in myoblasts results in a reduced proliferation and migration [27][28].

3. Interleukin-8 (IL-8)

In muscle from COPD patients, IL-8 has been reported as unchanged at the transcriptional level (at both stable and exacerbation states) compared to that of healthy controls [6]. Surprisingly, despite an important role for IL-8 in COPD pathophysiology and in particular lung inflammation, few data are available regarding its expression in the skeletal muscles of COPD patients.

4. Interleukin-18 (IL-18)

One study has found an elevation of IL-18, another proinflammatory cytokine, in the plasma and the quadriceps of COPD patients (at the mRNA level) compared to healthy controls [29]. Immunohistochemistry showed that the increase was predominant in type II fibers. Of note, muscle mRNA levels of TNF-α and IL-6 were unchanged in that study. Moreover, IL-18 mRNA levels were not significantly different in the quadriceps of COPD patients compared to that of healthy smokers. Of note, contrary to IL-6, IL-18 was not altered by exercise [29]. It was hypothesized that this increase could participate in skeletal muscle wasting by increasing local apoptosis.

5. Interleukin-15 (IL-15)

In vitro, IL-15 has an anabolic effect by inducing myosin chain synthesis in myotubes [30], notably in response to TNF-α stimulation [31]. This is particularly interesting given that IL-15 was increased and correlated with TNF-α in a rat model of COPD (induced by CS exposure as well as LPS instillations), in the serum and in both peripheral and respiratory skeletal muscles [32]. In the same study, this was paralleled by an increase in ubiquitin–proteasome markers (as expected), which were positively correlated to IL-15 levels. Furthermore, IL-15 possibly promotes the effector function of memory CD8+ T cells [33]. However, no data have been reported in human COPD muscle samples to the best of our knowledge.

6. Interferon-γ (IFN-γ)

IFN-γ has been reported as unchanged at the protein level in COPD quadriceps compared to controls [5]. However, a recent transcriptional analysis shows a globally downregulated interferon response in COPD quadriceps [34]. In vitro, IFN-γ does not activate catabolic pathways on C2C12 myoblasts [35] but induces the expression of proangiogenic factors such as angiopoietin-2 in primary human myoblasts [36]. Taken together, these data may indicate that IFN-γ downregulation could be part of the pathological mechanisms leading to skeletal muscle wasting, although other observational as well as functional data lack at this stage.

7. Interleukin-10 (IL-10)

IL-10 exerts a consistent anti-inflammatory, pro-regenerative role (as demonstrated by acute injury models). It bears potent anabolic effects by inhibiting the atrophy signaling induced by TNF-α in myotubes [37]. As a cytokine implicated in muscle regeneration in acute injury models (see below), its potential protective role in muscular dystrophy is not surprising [38]. However, to date, it has not been studied in skeletal muscles of COPD patients.

8. Other Myokines

Other myokines can also play a role in the control of muscle mass, most of which having not been thoroughly investigated in COPD, such as IL-4 (promoting myoblast fusion in vitro) [39], IL-7, which secretion by skeletal muscle gradually decreases with age [40], or irisin, known to decrease oxidant-induced apoptosis in diabetes mellitus, and recently reported to be decreased in COPD serum [41]. Two studies outside the COPD context also point towards a prominent role of the Toll-like receptor (TLR)-4 pathway in muscle wasting, via the activation of the p38-MAPK atrophy pathway [42][43]. However, to date, the expression of IL-17, a cytokine activating TLR4 signaling, has not been investigated in COPD muscle.

References

  1. Kochetkova, E.A.; Nevzorova, V.A.; Ugai, L.G.; Maistrovskaia, Y.V.; Massard, G. The Role of Tumor Necrosis Factor Alpha and TNF Superfamily Members in Bone Damage in Patients with End-Stage Chronic Obstructive Lung Disease Prior to Lung Transplantation. Calcif. Tissue Int. 2016, 99, 578–587.
  2. Wouters, E.F.M.; Creutzberg, E.C.; Schols, A.M.W.J. Systemic Effects in COPD. Chest 2002, 121, 127S–130S.
  3. Ferrari, R.; Caram, L.M.O.; Faganello, M.M.; Sanchez, F.F.; Tanni, S.E.; Godoy, I. Relation between Systemic Inflammatory Markers, Peripheral Muscle Mass, and Strength in Limb Muscles in Stable COPD Patients. Int. J. Chronic Obstr. Pulm. Dis. 2015, 10, 1553–1558.
  4. Eagan, T.M.; Gabazza, E.C.; D’Alessandro-Gabazza, C.; Gil-Bernabe, P.; Aoki, S.; Hardie, J.A.; Bakke, P.S.; Wagner, P.D. TNF-α Is Associated with Loss of Lean Body Mass Only in Already Cachectic COPD Patients. Respir. Res. 2012, 13, 48.
  5. Barreiro, E.; Schols, A.M.W.J.; Polkey, M.I.; Galdiz, J.B.; Gosker, H.R.; Swallow, E.B.; Coronell, C.; Gea, J. Cytokine Profile in Quadriceps Muscles of Patients with Severe COPD. Thorax 2008, 63, 100–107.
  6. Crul, T.; Spruit, M.A.; Gayan-Ramirez, G.; Quarck, R.; Gosselink, R.; Troosters, T.; Pitta, F.; Decramer, M. Markers of Inflammation and Disuse in Vastus Lateralis of Chronic Obstructive Pulmonary Disease Patients. Eur. J. Clin. Investig. 2007, 37, 897–904.
  7. De Oca, M.M.; Torres, S.H.; Sanctis, J.D.; Mata, A.; Hernández, N.; Tálamo, C. Skeletal Muscle Inflammation and Nitric Oxide in Patients with COPD. Eur. Respir. J. 2005, 26, 390–397.
  8. Koechlin, C.; Maltais, F.; Saey, D.; Michaud, A.; LeBlanc, P.; Hayot, M.; Préfaut, C. Hypoxaemia Enhances Peripheral Muscle Oxidative Stress in Chronic Obstructive Pulmonary Disease. Thorax 2005, 60, 834–841.
  9. Remels, A.H.V.; Gosker, H.R.; Schrauwen, P.; Hommelberg, P.P.H.; Sliwinski, P.; Polkey, M.; Galdiz, J.; Wouters, E.F.M.; Langen, R.C.J.; Schols, A.M.W.J. TNF-α Impairs Regulation of Muscle Oxidative Phenotype: Implications for Cachexia? FASEB J. 2010, 24, 5052–5062.
  10. De Paepe, B.; Brusselle, G.G.; Maes, T.; Creus, K.K.; D’hose, S.; D’Haese, N.; Bracke, K.R.; D’hulst, A.I.; Joos, G.F.; De Bleecker, J.L. TNF Alpha Receptor Genotype Influences Smoking-Induced Muscle-Fibre-Type Shift and Atrophy in Mice. Acta Neuropathol. 2008, 115, 675–681.
  11. Steffen, B.T.; Lees, S.J.; Booth, F.W. Anti-TNF Treatment Reduces Rat Skeletal Muscle Wasting in Monocrotaline-Induced Cardiac Cachexia. J. Appl. Physiol. 2008, 105, 1950–1958.
  12. Wang, Y.; Welc, S.S.; Wehling-Henricks, M.; Tidball, J.G. Myeloid Cell-Derived Tumor Necrosis Factor-Alpha Promotes Sarcopenia and Regulates Muscle Cell Fusion with Aging Muscle Fibers. Aging Cell 2018, 17, e12828.
  13. Passey, S.L.; Bozinovski, S.; Vlahos, R.; Anderson, G.P.; Hansen, M.J. Serum Amyloid A Induces Toll-Like Receptor 2-Dependent Inflammatory Cytokine Expression and Atrophy in C2C12 Skeletal Muscle Myotubes. PLoS ONE 2016, 11, e0146882.
  14. Remels, A.H.V.; Gosker, H.R.; Verhees, K.J.P.; Langen, R.C.J.; Schols, A.M.W.J. TNF-α-Induced NF-ΚB Activation Stimulates Skeletal Muscle Glycolytic Metabolism through Activation of HIF-1α. Endocrinology 2015, 156, 1770–1781.
  15. To, M.; Swallow, E.B.; Akashi, K.; Haruki, K.; Natanek, S.A.; Polkey, M.I.; Ito, K.; Barnes, P.J. Reduced HDAC2 in Skeletal Muscle of COPD Patients. Respir. Res. 2017, 18, 99.
  16. Li, Y.-P. TNF-Alpha Is a Mitogen in Skeletal Muscle. Am. J. Physiol. Cell Physiol. 2003, 285, C370–C376.
  17. Tidball, J.G. Regulation of Muscle Growth and Regeneration by the Immune System. Nat. Rev. Immunol. 2017, 17, 165–178.
  18. Bakkar, N.; Wang, J.; Ladner, K.J.; Wang, H.; Dahlman, J.M.; Carathers, M.; Acharyya, S.; Rudnicki, M.A.; Hollenbach, A.D.; Guttridge, D.C. IKK/NF-KappaB Regulates Skeletal Myogenesis via a Signaling Switch to Inhibit Differentiation and Promote Mitochondrial Biogenesis. J. Cell Biol. 2008, 180, 787–802.
  19. Tang, K.; Wagner, P.D.; Breen, E.C. TNF-Alpha-Mediated Reduction in PGC-1alpha May Impair Skeletal Muscle Function after Cigarette Smoke Exposure. J. Cell. Physiol. 2010, 222, 320–327.
  20. Tang, K.; Murano, G.; Wagner, H.; Nogueira, L.; Wagner, P.D.; Tang, A.; Dalton, N.D.; Gu, Y.; Peterson, K.L.; Breen, E.C. Impaired Exercise Capacity and Skeletal Muscle Function in a Mouse Model of Pulmonary Inflammation. J. Appl. Physiol. 2013, 114, 1340–1350.
  21. Aaron, S.D.; Vandemheen, K.L.; Maltais, F.; Field, S.K.; Sin, D.D.; Bourbeau, J.; Marciniuk, D.D.; FitzGerald, J.M.; Nair, P.; Mallick, R. TNFα Antagonists for Acute Exacerbations of COPD: A Randomised Double-Blind Controlled Trial. Thorax 2013, 68, 142–148.
  22. Sin, D.D.; Man, S.F.P. Interleukin-6: A Red Herring or a Real Catch in COPD? Chest 2008, 133, 4–6.
  23. Yende, S.; Waterer, G.W.; Tolley, E.A.; Newman, A.B.; Bauer, D.C.; Taaffe, D.R.; Jensen, R.; Crapo, R.; Rubin, S.; Nevitt, M.; et al. Inflammatory Markers Are Associated with Ventilatory Limitation and Muscle Dysfunction in Obstructive Lung Disease in Well Functioning Elderly Subjects. Thorax 2006, 61, 10–16.
  24. Belizário, J.E.; Fontes-Oliveira, C.C.; Borges, J.P.; Kashiabara, J.A.; Vannier, E. Skeletal Muscle Wasting and Renewal: A Pivotal Role of Myokine IL-6. SpringerPlus 2016, 5, 619.
  25. Tsujinaka, T.; Fujita, J.; Ebisui, C.; Yano, M.; Kominami, E.; Suzuki, K.; Tanaka, K.; Katsume, A.; Ohsugi, Y.; Shiozaki, H.; et al. Interleukin 6 Receptor Antibody Inhibits Muscle Atrophy and Modulates Proteolytic Systems in Interleukin 6 Transgenic Mice. J. Clin. Investig. 1996, 97, 244–249.
  26. Williams, A.; Wang, J.J.; Wang, L.; Sun, X.; Fischer, J.E.; Hasselgren, P.O. Sepsis in Mice Stimulates Muscle Proteolysis in the Absence of IL-6. Am. J. Physiol. 1998, 275, R1983–R1991.
  27. Baeza-Raja, B.; Muñoz-Cánoves, P. P38 MAPK-Induced Nuclear Factor-KappaB Activity Is Required for Skeletal Muscle Differentiation: Role of Interleukin-6. Mol. Biol. Cell 2004, 15, 2013–2026.
  28. Serrano, A.L.; Baeza-Raja, B.; Perdiguero, E.; Jardí, M.; Muñoz-Cánoves, P. Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle Hypertrophy. Cell Metab. 2008, 7, 33–44.
  29. Petersen, A.M.W.; Penkowa, M.; Iversen, M.; Frydelund-Larsen, L.; Andersen, J.L.; Mortensen, J.; Lange, P.; Pedersen, B.K. Elevated Levels of IL-18 in Plasma and Skeletal Muscle in Chronic Obstructive Pulmonary Disease. Lung 2007, 185, 161–171.
  30. Quinn, L.S.; Anderson, B.G.; Drivdahl, R.H.; Alvarez, B.; Argilés, J.M. Overexpression of Interleukin-15 Induces Skeletal Muscle Hypertrophy in Vitro: Implications for Treatment of Muscle Wasting Disorders. Exp. Cell Res. 2002, 280, 55–63.
  31. O’Leary, M.F.; Wallace, G.R.; Bennett, A.J.; Tsintzas, K.; Jones, S.W. IL-15 Promotes Human Myogenesis and Mitigates the Detrimental Effects of TNFα on Myotube Development. Sci. Rep. 2017, 7, 12997.
  32. Liu, Z.; Fan, W.; Chen, J.; Liang, Z.; Guan, L. The Role of Interleukin 15 in Protein Degradation in Skeletal Muscles in Rats of Chronic Obstructive Pulmonary Disease. Int. J. Clin. Exp. Med. 2015, 8, 1976–1984.
  33. Huang, P.-L.; Hou, M.-S.; Wang, S.-W.; Chang, C.-L.; Liou, Y.-H.; Liao, N.-S. Skeletal Muscle Interleukin 15 Promotes CD8+ T-Cell Function and Autoimmune Myositis. Skelet. Muscle 2015, 5, 33.
  34. Tényi, Á.; Cano, I.; Marabita, F.; Kiani, N.; Kalko, S.G.; Barreiro, E.; de Atauri, P.; Cascante, M.; Gomez-Cabrero, D.; Roca, J. Network Modules Uncover Mechanisms of Skeletal Muscle Dysfunction in COPD Patients. J. Transl. Med. 2018, 16, 34.
  35. Smith, M.A.; Moylan, J.S.; Smith, J.D.; Li, W.; Reid, M.B. IFN-γ Does Not Mimic the Catabolic Effects of TNF-α. Am. J. Physiol. Cell Physiol. 2007, 293, C1947–C1952.
  36. Mofarrahi, M.; Sigala, I.; Vassilakopoulos, T.; Harel, S.; Guo, Y.; Debigare, R.; Maltais, F.; Hussain, S.N.A. Angiogenesis-Related Factors in Skeletal Muscles of COPD Patients: Roles of Angiopoietin-2. J. Appl. Physiol. 2013, 114, 1309–1318.
  37. Strle, K.; McCusker, R.H.; Johnson, R.W.; Zunich, S.M.; Dantzer, R.; Kelley, K.W. Prototypical Anti-Inflammatory Cytokine IL-10 Prevents Loss of IGF-I-Induced Myogenin Protein Expression Caused by IL-1beta. Am. J. Physiol. Endocrinol. Metab. 2008, 294, E709–E718.
  38. Villalta, S.A.; Rinaldi, C.; Deng, B.; Liu, G.; Fedor, B.; Tidball, J.G. Interleukin-10 Reduces the Pathology of Mdx Muscular Dystrophy by Deactivating M1 Macrophages and Modulating Macrophage Phenotype. Hum. Mol. Genet. 2011, 20, 790–805.
  39. Horsley, V.; Jansen, K.M.; Mills, S.T.; Pavlath, G.K. IL-4 Acts as a Myoblast Recruitment Factor during Mammalian Muscle Growth. Cell 2003, 113, 483–494.
  40. Nelke, C.; Dziewas, R.; Minnerup, J.; Meuth, S.G.; Ruck, T. Skeletal Muscle as Potential Central Link between Sarcopenia and Immune Senescence. EBioMedicine 2019, 49, 381–388.
  41. Sugiyama, Y.; Asai, K.; Yamada, K.; Kureya, Y.; Ijiri, N.; Watanabe, T.; Kanazawa, H.; Hirata, K. Decreased Levels of Irisin, a Skeletal Muscle Cell-Derived Myokine, Are Related to Emphysema Associated with Chronic Obstructive Pulmonary Disease. Int. J. Chronic Obstr. Pulm. Dis. 2017, 12, 765–772.
  42. Doyle, A.; Zhang, G.; Fattah, E.A.A.; Eissa, N.T.; Li, Y.-P. Toll-like Receptor 4 Mediates Lipopolysaccharide-Induced Muscle Catabolism via Coordinate Activation of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways. FASEB J. 2011, 25, 99–110.
  43. Tang, H.; Pang, S.; Wang, M.; Xiao, X.; Rong, Y.; Wang, H.; Zang, Y.Q. TLR4 Activation Is Required for IL-17–Induced Multiple Tissue Inflammation and Wasting in Mice. J. Immunol. 2010, 185, 2563–2569.
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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Pauline Henrot
,
Isabelle Dupin
,
Pierre Schilfarth
,
Pauline Esteves
,
Léo Blervaque
,
Maéva Zysman
,
Fares Gouzi
,
Maurice Hayot
,
Pascal Pomiès
,
Patrick Berger
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Update Date: 18 Aug 2023
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