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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: (accessed on 22 June 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: Accessed June 22, 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, (accessed June 22, 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.
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

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.


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