Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

In the paper

“While some authors have found an increased COX activity in COPD patients with resting hypoxemia [96] and with exercise hypoxemia [97], others have not found any significant increase [98].”

What the sources say

• ?Not checked — no full text of the sourcecites [96] Sauleda, 1998, Cytochrome Oxidase Activity and Mitochondrial Gene Expression in Skeletal Muscle of Patients with Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. source
• Disputed

  The citation [98] supports the clause saying that others found no significant increase in COX activity. In the Mitochondrial function section, this paper instead reports significantly higher COX activity in COPD patients than in controls in both muscles studied; the Previous studies section says its results agree with an earlier report of increased COX activity. The supplied passages do not give page numbers. (LLM, conf=0.93)

  Checked by a reasoning model — may be wrong.

  cites [97] Godoy, 2009, Abnormal Mitochondrial Function in Locomotor and Respiratory Muscles of COPD Patients, Eur. Respir. J. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [98] Picard, 2008, The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease: Disuse or Dysfunction?, Am. J. Respir. Crit. Care Med. source

In the paper

“COPD should not be limited to its respiratory features and is now considered as a systemic inflammatory disease implicating a wild range of cytokines and chemokines [5] and including several comorbidities.”

What the sources say

• Partly supported

  The Introduction identifies chemokines as cytokines with a pivotal role in COPD, and §3 describes chemokines produced in both the lung and systemic circulation. But §3.3.2 describes a systemic inflammatory response specifically during virus-associated exacerbations; it does not establish the broader characterization of COPD as a systemic inflammatory disease. The comorbidities phrase follows the citation and is not assessed as attributed to this source. (LLM, conf=0.82)

  cites [5] Henrot, P., Prevel, R., Berger, P., and Dupin, I. (2019). Chemokines in COPD: From Implication to Therapeutic Use. Int. J. Mol. Sci., 20. sourceExperimental — accuracy not yet measured

In the paper

“Structural alterations of peripheral skeletal muscle are well characterized and include a global muscle atrophy (with both loss in number and size of muscle fibers), macroscopically reflected by a decrease in thigh diameter [11] and microscopically reflected by a decreased fibers’ cross-sectional area (CSA) [12]”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Bernard, 1998, Peripheral Muscle Weakness in Patients with Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. source
• Supported

  Citation [12] is attached to the microscopic finding of decreased muscle-fiber cross-sectional area, not the separate thigh-diameter claim cited to [11]. The Results report lower overall mean fiber CSA in patients with COPD than in controls, with the reduction concentrated in IIA/IIX and IIX fibers. Page numbers were not available in our copy. (LLM, conf=0.93)

  cites [12] Gosker, 2002, Muscle Fiber Type IIX Atrophy Is Involved in the Loss of Fat-Free Mass in Chronic Obstructive Pulmonary Disease, Am. J. Clin. Nutr. source

In the paper

“with regards to muscular TNF-α, significantly elevated, decreased, and unaltered levels have been reported in the quadriceps of COPD patients [27,28,29], or even undetected at the protein level [30,31]”

What the sources say

• Supported

  The Discussion and ELISA results report significantly reduced quadriceps TNF-α protein levels in patients with severe COPD compared with controls. This supports the 'decreased' finding in the sentence’s list of reports; the other findings are attributed to other citations. (LLM, conf=0.94)

  cites [27] Barreiro, 2008, Cytokine Profile in Quadriceps Muscles of Patients with Severe COPD, Thorax source
• ?Not checked — no full text of the sourcecites [28] Crul, 2007, Markers of Inflammation and Disuse in Vastus Lateralis of Chronic Obstructive Pulmonary Disease Patients, Eur. J. Clin. Investig. source
• Supported

  The Muscle biopsy section identifies the sampled muscle as the vastus lateralis of the quadriceps. The Results report markedly higher skeletal-muscle TNF-α in COPD patients than in healthy controls, supporting the elevated-level finding for which this source is cited. The other findings in the citing sentence are accompanied by other citations. (LLM, conf=0.92)

  cites [29] Torres, 2005, Skeletal Muscle Inflammation and Nitric Oxide in Patients with COPD, Eur. Respir. J. source
• Supported

  The citation to this paper supports the clause about TNF-α being undetected, not the differing levels attributed to [27–29]. The Inflammatory markers section reports that muscle TNF-α was not detected by immunostaining in quadriceps biopsy specimens, either at rest or after exercise, in either COPD group. (LLM, conf=0.94)

  cites [30] Koechlin, 2005, Hypoxaemia Enhances Peripheral Muscle Oxidative Stress in Chronic Obstructive Pulmonary Disease, Thorax source
• ?Could not verify

  The retrieved copy contains the paper’s title and bibliographic material (section labeled Abstract, no page), but no passage about quadriceps TNF-α levels in COPD patients. Searches for elevated, decreased, unaltered, and undetected muscle TNF-α did not find evidence to assess the claim. (LLM, conf=0.70)

  cites [31] Remels, 2010, TNF-α Impairs Regulation of Muscle Oxidative Phenotype: Implications for Cachexia?, FASEB J. sourceExperimental — accuracy not yet measured

In the paper

“Circulating IL-6 is also classically elevated in COPD patients compared to healthy subjects, both during and outside exacerbations [44] and associated with reduced quadriceps strength [45].”

What the sources say

• Partly supported

  The Interleukin-6 section links circulating IL-6 to COPD exacerbations, and the References list a study reporting elevated serum IL-6 during acute exacerbations. But its comparison with healthy controls during clinical stability concerns CRP, fibrinogen, leukocytes, and platelets—not IL-6—so it does not establish that part of the claim. Reduced quadriceps strength has a separate citation [45] in the citing sentence and is not judged against this source. (LLM, conf=0.83)

  cites [44] Sin, 2008, Interleukin-6: A Red Herring or a Real Catch in COPD?, Chest sourceExperimental — accuracy not yet measured
• Supported

  Citation [45] is attached to the association with reduced quadriceps strength, not the preceding claim about IL-6 during and outside exacerbations. The Discussion reports that IL-6 levels were inversely associated with quadriceps strength in participants with stable obstructive lung disease; the study population was well-functioning older adults. (LLM, conf=0.92)

  cites [45] Yende, 2006, Inflammatory Markers Are Associated with Ventilatory Limitation and Muscle Dysfunction in Obstructive Lung Disease in Well Functioning Elderly Subjects, Thorax source

In the paper

“Chronic, low-grade inflammation induces muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secretome [20], whereas acute inflammation (exercise-mediated or in acute muscle injury models) activates anabolic pathways leading to muscle regeneration.”

What the sources say

• Supported

  The cited paper’s section “Sarcopenia and immune senescence: a bidirectional link” states the clause immediately preceding citation [20] nearly verbatim. The acute-inflammation clause follows the citation and is not attributed to this source by that citation. (LLM, conf=0.95)

  cites [20] Nelke, 2019, Skeletal Muscle as Potential Central Link between Sarcopenia and Immune Senescence, EBioMedicine source

In the paper

“The authors also evidenced a decrease of HDAC2 level in the quadriceps of COPD patients, associated with an increase in the NF-кB pathway.”

What the sources say

• Supported

  The Abstract’s Methods and results report significantly lower HDAC2 protein in quadriceps biopsies from COPD patients and significantly higher NF-κB DNA-binding activity, which correlated with the HDAC2 decrease. The Discussion likewise describes increased NF-κB activity in skeletal muscle from COPD patients. (LLM, conf=0.94)

  cites [37] To, 2017, Reduced HDAC2 in Skeletal Muscle of COPD Patients, Respir. Res. source

In the paper

“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 [39]”

What the sources say

• Partly supported

  In “Muscle–myeloid cell interactions during the early, proliferative stage of muscle regeneration” (page unavailable), the review describes TNF signalling through p38α repressing PAX7 via EZH2 and promoting differentiation of myogenic precursor cells. The same section describes TNF-induced epigenetic silencing of NOTCH1, but does not establish that p38α mediates that silencing; it also does not specify TNF-receptor binding as the initiating step or directly link this pathway to myotube formation. (LLM, conf=0.85)

  cites [39] Tidball, 2017, Regulation of Muscle Growth and Regeneration by the Immune System, Nat. Rev. Immunol. sourceExperimental — accuracy not yet measured

In the paper

“However, inflammation is not the sole driver as exercise can affect factors regulating muscle hypertrophy and regeneration without affecting the levels of systemic or local muscle inflammation [19].”

What the sources say

• Supported

  The Discussion reports that exercise training increased factors regulating muscle hypertrophy and regeneration in patients with COPD while neither systemic inflammatory mediator levels nor local muscle TNFα and IL-6 expression decreased. This supports the claim that muscle adaptation can occur without a reduction in the measured inflammation markers. No page number is provided in our copy. (LLM, conf=0.93)

  cites [19] Vogiatzis, 2007, Effects of Rehabilitative Exercise on Peripheral Muscle TNFalpha, IL-6, IGF-I and MyoD Expression in Patients with COPD, Thorax source

In the paper

“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.”

What the sources say

• Supported

  The Subjects section identifies the samples as quadriceps muscle biopsies from COPD patients. The results section reports elevated HIF-1α and VEGF mRNA compared with controls, with the increases most pronounced in patients with high muscle TNF-α; the Discussion describes this as an association. The source supports the claimed relationship, though it reports expression and association rather than a formal correlation of each marker with TNF-α. (LLM, conf=0.90)

  cites [36] Remels, 2015, TNF-α-Induced NF-ΚB Activation Stimulates Skeletal Muscle Glycolytic Metabolism through Activation of HIF-1α, Endocrinology source

In the paper

“therapies against TNF-α have not proven to be effective for various outcomes such as dyspnea or a number of exacerbations [43], suggesting that this cytokine is not the primary or at least the sole driver of COPD inflammation.”

What the sources say

• Partly supported

  The Secondary outcomes section (page unavailable) reports that dyspnoea improved in both groups, with no significant difference between etanercept and prednisone. The Discussion (page unavailable) also reports no benefit of etanercept over prednisone for treating acute exacerbations and cites a separate trial finding no dyspnoea benefit from infliximab in stable COPD. This paper does not establish that TNF-α therapies reduce the number of exacerbations; its own trial studied treatment of an exacerbation, not prevention of future ones. (LLM, conf=0.86)

  cites [43] Aaron, 2013, TNFα Antagonists for Acute Exacerbations of COPD: A Randomised Double-Blind Controlled Trial, Thorax sourceExperimental — accuracy not yet measured

In the paper

“the pilot study of Tsujinaka and colleagues showed that transgenic mice chronically overexpressing IL-6 exhibit a marked muscle atrophy [47]; however, the knockout of IL-6 was not sufficient to prevent sarcopenia in a sepsis mouse model [48].”

What the sources say

• Supported

  The Discussion states that chronic IL-6 overproduction in transgenic mice causes muscle weight loss, and the Abstract reports muscle atrophy in those mice. The sepsis-model knockout finding has a separate citation [48] and is not attributed to this paper. (LLM, conf=0.93)

  cites [47] Tsujinaka, 1996, Interleukin 6 Receptor Antibody Inhibits Muscle Atrophy and Modulates Proteolytic Systems in Interleukin 6 Transgenic Mice, J. Clin. Investig. source
• ?Not checked — no full text of the sourcecites [48] Williams, 1998, Sepsis in Mice Stimulates Muscle Proteolysis in the Absence of IL-6, Am. J. Physiol. source

In the paper

“Adipose tissue infiltration has also been reported in COPD muscle, in a similar way to senescent muscle in the aging population, particularly in the obese sarcopenic phenotype where adipose inflammation leads to the redistribution of fat to the intra-abdominal area and skeletal muscle tissue [16,17]”

What the sources say

• Partly supported

  The Introduction defines muscle fat infiltration in COPD, and the Discussion reports excess thigh-muscle fat infiltration and visceral adipose tissue in the COPD cohort. The paper does not establish that infiltration occurs particularly in an obese sarcopenic phenotype or that adipose inflammation causes fat to redistribute into the abdomen and muscle. Instead, it describes those fat deposits as possible sources of systemic inflammation. (LLM, conf=0.88)

  cites [16] Persson, 2022, Skeletal Myosteatosis Is Associated with Systemic Inflammation and a Loss of Muscle Bioenergetics in Stable COPD, J. Inflamm. Res. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Figure 2 caption describe ageing-related adipose inflammation redistributing fat to visceral depots and skeletal muscle, with a possible contribution to sarcopenic obesity (page numbers unavailable). The section on chronic disease mentions muscle fat infiltration in COPD, but specifically discusses lean patients; it does not establish that this process occurs particularly in an obese sarcopenic COPD phenotype. (LLM, conf=0.88)

  cites [17] Li, 2022, Pathogenesis of Sarcopenia and the Relationship with Fat Mass: Descriptive Review, J. Cachexia Sarcopenia Muscle sourceExperimental — accuracy not yet measured

In the paper

“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 [41].”

What the sources say

• Supported

  The Discussion (Early COPD-like locomotor skeletal muscle phenotype; page unavailable) reports higher circulating TNF-α in smoke-exposed mice alongside reduced capillarity and atrophy-related gene expression. The Discussion summary also reports muscle atrophy, while the Results (Gene expression of muscle ubiquitin ligases; page unavailable) document increases in atrogin-1 and MuRF-1, supporting the claim’s reference to catabolic changes. (LLM, conf=0.87)

  cites [41] Tang, 2010, TNF-Alpha-Mediated Reduction in PGC-1alpha May Impair Skeletal Muscle Function after Cigarette Smoke Exposure, J. Cell. Physiol. source

In the paper

“IFN-γ has been reported as unchanged at the protein level in COPD quadriceps compared to controls [27]. However, a recent transcriptional analysis shows a globally downregulated interferon response in COPD quadriceps [56].”

What the sources say

• Supported

  The “Expression of IL6, Interferon c and TGFb” section reports no significant difference in quadriceps interferon-γ protein levels between patients with COPD and controls, measured by ELISA. The separate transcriptional-analysis statement cites [56], not this source. (LLM, conf=0.94)

  cites [27] Barreiro, 2008, Cytokine Profile in Quadriceps Muscles of Patients with Severe COPD, Thorax source
• Partly supported

  The Results section on skeletal muscle alterations at rest reports systematic down-regulation of IFIT genes in an interferon-response module. The Methods identify the sampled muscle as the vastus lateralis, part of the quadriceps. The paper does not establish that the interferon response as a whole was globally downregulated; the separate protein-level claim is cited to [27], not this source. (LLM, conf=0.82)

  cites [56] Cano, 2018, Network Modules Uncover Mechanisms of Skeletal Muscle Dysfunction in COPD Patients, J. Transl. Med. sourceExperimental — accuracy not yet measured

In the paper

“a recent study pointed out a possible role of intermittent hypoxia (such as the nocturnal hypoxemia seen in obstructive sleep apnea disorder, frequent among COPD patients [83]) in skeletal muscle wasting, driven by mitochondrial dysfunction and a lower activity [84].”

What the sources say

• Partly supported

  The Results report smaller myotube diameter during prolonged intermittent hypoxia and reduced mitochondrial oxidative function and respiratory-chain complex activity. The paper does not establish lower physical activity as a driver of muscle wasting; its reported lower activity is mitochondrial complex activity. It also distinguishes its prolonged nocturnal-hypoxia model from the brief episodes typical of obstructive sleep apnea. (LLM, conf=0.82)

  cites [84] Attaway, 2022, Adaptive Exhaustion during Prolonged Intermittent Hypoxia Causes Dysregulated Skeletal Muscle Protein Homeostasis, J. Physiol. sourceExperimental — accuracy not yet measured

In the paper

“The same authors confirmed their observations in 2017 on a different cohort of COPD patients matched to healthy controls based on the same physical activity, in order to avoid disuse bias. They observed a diminished state 3 CI-driven respiration, and a trend to a lower state 3:CI+CII driven respiration.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [101] Gifford, 2015, Quadriceps Exercise Intolerance in Patients with Chronic Obstructive Pulmonary Disease: The Potential Role of Altered Skeletal Muscle Mitochondrial Respiration, J. Appl. Physiol. sourceExperimental — accuracy not yet measured

In the paper

“they concluded that this reduction was largely driven by diminished CI-driven respiration rather than CII-driven respiration.”

What the sources say

• Supported

  The section “CI vs. CII-driven respiration in COPD” explicitly states that the reduction in State 3:CI+CII in patients with COPD was largely driven by diminished CI-driven, rather than CII-driven, respiration. It also reports that State 3:CI was significantly reduced compared with controls while State 3:CII was not. (LLM, conf=0.95)

  cites [101] Gifford, 2015, Quadriceps Exercise Intolerance in Patients with Chronic Obstructive Pulmonary Disease: The Potential Role of Altered Skeletal Muscle Mitochondrial Respiration, J. Appl. Physiol. source

In the paper

“Importantly, transfecting the defective CII subunit C to mice muscles significantly increased both mitochondrial function (respiration) and oxidative myofibers’ proportion, indicating that mitochondrial function could regulate the muscle fiber phenotype in vivo.”

What the sources say

• Supported

  In the in vivo overexpression section (page unavailable), the paper reports significantly increased oxygen consumption after SDHC electroporation in IL13 transgenic mouse muscle. The fiber-type section (page unavailable) reports more oxidative type 2A and 2X fibers and fewer type 2B fibers, while cautiously suggesting that fiber identity could change downstream of increased oxidative capacity. The intervention restored expression of downregulated SDHC; the paper does not describe transfecting a defective SDHC construct. (LLM, conf=0.88)

  cites [102] Balnis, 2021, Succinate Dehydrogenase (SDH)-Subunit C Regulates Muscle Oxygen Consumption and Fatigability in an Animal Model of Pulmonary Emphysema, Am. J. Respir. Cell Mol. Biol. source

In the paper

“only one study investigated HIF-1α expression and found an increased mRNA level in the quadriceps of COPD patients, related to increased TNF-α signaling [36].”

What the sources say

• Supported

  The Subjects section identifies quadriceps biopsies from COPD patients and healthy controls. The HIF-1α and VEGF results section reports higher muscle HIF-1α mRNA in COPD patients, most pronounced in those with high muscle TNF-α; the Discussion describes this as an association with TNF-α expression. (LLM, conf=0.90)

  cites [36] Remels, 2015, TNF-α-Induced NF-ΚB Activation Stimulates Skeletal Muscle Glycolytic Metabolism through Activation of HIF-1α, Endocrinology source

In the paper

“Hypoxia seems to play a prominent role in the skeletal muscle wasting of COPD patients, as suggested by a network-analysis transcriptomic studies evidencing upregulation of four histone deacetylase in the muscle of COPD patients (HDAC 9 and 4, SIRT 2 and 3) compared to that of healthy subjects and correlated with oxygen availability [66].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [66] Turan, N., Kalko, S., Stincone, A., Clarke, K., Sabah, A., Howlett, K., Curnow, S.J., Rodriguez, D.A., Cascante, M., and O’Neill, L. (2011). A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease. PLoS Comput. Biol., 7. sourceExperimental — accuracy not yet measured

In the paper

“The expressions of electron transport chain (ETC) complex proteins I, II, III, and V have, for example, been reported as unchanged in patients with mild COPD (GOLD II) but decreased in patients with severe or very severe COPD (GOLD III-IV) [89].”

What the sources say

• Partly supported

  The Results section on quadriceps muscle reports unchanged levels of ETC complex proteins I, II, III and V in GOLD Grade 2 patients and significantly reduced levels in GOLD Grade 3/4 patients. The claim omits that this pattern is specific to quadriceps muscle: the airway Results report reduced complex I and II expression in GOLD Grade 2 patients. (LLM, conf=0.86)

  cites [89] Haji, 2020, COPDMAP consortium Mitochondrial Dysfunction in Airways and Quadriceps Muscle of Patients with Chronic Obstructive Pulmonary Disease, Respir. Res. sourceExperimental — accuracy not yet measured

In the paper

“A study showed that exercise training improved functional capacity in both normoxemic and hypoxemic COPD patients, however the structural improvements (increased mitochondrial density, capillary-to-fiber ratio, and fibers’ CSA) occurred only in the normoxemic ones [80].”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [80] Costes, 2015, Impaired Exercise Training-Induced Muscle Fiber Hypertrophy and Akt/MTOR Pathway Activation in Hypoxemic Patients with COPD, J. Appl. Physiol. sourceExperimental — accuracy not yet measured

In the paper

“Only one study investigated dynamin-1-like protein DNML1 (also known as DRP1, a GTPase regulating mitochondrial fission) expression in COPD quadriceps and found a decreased protein level [88].”

What the sources say

• Supported

  The Results section reports that DNM1L protein levels were lower in the vastus lateralis (a quadriceps muscle) of patients with COPD than in controls. The Introduction identifies DNM1L as DRP1. The phrase “only one study” describes the citing authors’ survey of the literature, rather than a finding this study needs to establish. (LLM, conf=0.92)

  cites [88] Leermakers, 2018, Molecular Signalling towards Mitochondrial Breakdown Is Enhanced in Skeletal Muscle of Patients with Chronic Obstructive Pulmonary Disease (COPD), Sci. Rep. source

In the paper

“Remels and colleagues observed low levels of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1-α, the master regulator of mitochondrial biogenesis) and its downstream effector, mitochondrial transcription factor A (TFAM), in COPD quadriceps; these differences were further enhanced in cachectic COPD patients [90].”

What the sources say

• Partly supported

  The Methods section identifies the biopsied muscle as quadriceps. The PGC-1a and TFAM results sections report lower PGC-1a mRNA and TFAM protein in COPD, with a further TFAM reduction in cachectic patients. But PGC-1a mRNA did not differ between cachectic and noncachectic patients, and PGC-1a protein was not measured; the claim overstates the cachexia finding for PGC-1a. (LLM, conf=0.93)

  cites [90] Remels, 2007, Peroxisome Proliferator-Activated Receptor Expression Is Reduced in Skeletal Muscle in COPD, Eur. Respir. J. sourceExperimental — accuracy not yet measured

In the paper

“During exacerbations, mitochondrial respiration seems to be further decreased, as confirmed by a study investigating the transcriptomic profile of quadriceps biopsies between exacerbating COPD patients and stable COPD controls, and evidencing a decreased aspartate catabolism as well as COX6C activity [104].”

What the sources say

• Partly supported

  The Discussion reports downregulated aspartate catabolism and mitochondrial respiratory-chain pathways in vastus lateralis muscle during exacerbation. The Real-time PCR data section reports lower COX6C mRNA in exacerbating patients than in stable COPD patients, but it does not establish decreased COX6C activity; that part of the claim overstates the measurement. (LLM, conf=0.88)

  cites [104] Crul, 2010, Gene Expression Profiling in Vastus Lateralis Muscle During an Acute Exacerbation of COPD, Cell. Physiol. Biochem. sourceExperimental — accuracy not yet measured

In the paper

“The evidence for DNA damage is scarce but includes higher (8-OHdG) levels in COPD quadriceps compared to controls [87].”

What the sources say

• Supported

  The Results section reports 50% higher 8-OHdG in COPD vastus lateralis muscle than in controls; the vastus lateralis is part of the quadriceps. The Discussion says oxidative damage to lipids and proteins had been measured most commonly and describes this as the first finding of higher 8-OHdG in COPD muscle, consistent with the claim that DNA-damage evidence was scarce. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [87] Konokhova, 2016, Failed Upregulation of TFAM Protein and Mitochondrial DNA in Oxidatively Deficient Fibers of Chronic Obstructive Pulmonary Disease Locomotor Muscle, Skelet. Muscle source

In the paper

“For example, several studies have found an increased lipofuscin accumulation in COPD quadriceps [126] and higher levels of hydroxy-2-nonenal (4-HNE) in quadriceps tissue [87,127], as well as in cultured myotubes from COPD patients [128].”

What the sources say

• ?Not checked — no full text of the sourcecites [126] Allaire, 2002, Lipofuscin Accumulation in the Vastus Lateralis Muscle in Patients with Chronic Obstructive Pulmonary Disease, Muscle Nerve source
• Supported

  The citation to this paper is attached to the higher 4-HNE levels in quadriceps tissue, not to lipofuscin or cultured myotubes. The Results section (‘Higher prevalence of oxidative damage and mtDNA deletions in COPD muscle’) reports that 4-hydroxynonenal adducts were twice as high in COPD vastus lateralis muscle as in age-matched controls. (LLM, conf=0.94)

  cites [87] Konokhova, 2016, Failed Upregulation of TFAM Protein and Mitochondrial DNA in Oxidatively Deficient Fibers of Chronic Obstructive Pulmonary Disease Locomotor Muscle, Skelet. Muscle source
• Supported

  This source is cited for the quadriceps-tissue 4-HNE finding, not the separately cited lipofuscin or cultured-myotube findings. The Muscle redox balance section reports significantly higher baseline HNE-protein adducts in COPD quadriceps than in controls. (LLM, conf=0.94)

  cites [127] Barreiro, 2009, Chronic Endurance Exercise Induces Quadriceps Nitrosative Stress in Patients with Severe COPD, Thorax source
• Partly supported

  The Results section reports higher measured 4-HNE levels in cultured myotubes from COPD patients than in controls, which supports the portion attributed to this paper. It describes the difference as a tendency (P = 0.065), however, so the unqualified claim of higher levels overstates the evidence. The lipofuscin and quadriceps-tissue claims have other citations. (LLM, conf=0.87)

  cites [128] Rodriguez, 2015, Reduced Myotube Diameter, Atrophic Signalling and Elevated Oxidative Stress in Cultured Satellite Cells from COPD Patients, J. Cell. Mol. Med. sourceExperimental — accuracy not yet measured

In the paper

“Finally, the antioxidant protein carnosine, mainly present in type II myofibers, has been reported to be unchanged in the muscle of COPD patients compared to healthy controls; however, in COPD patients, carnosine was decreased in the quadriceps of GOLD III–IV patients compared to GOLD I–II, despite their increased proportion of type II myofibers [125].”

What the sources say

• Supported

  The paper’s conclusion and New & Noteworthy passage state that quadriceps carnosine was similar in patients with COPD and healthy controls. They also report 31% lower carnosine in severe/very severe than mild/moderate COPD, despite a high proportion of fast-twitch fibers. No page number is available in our copy. (LLM, conf=0.93)

  cites [125] Burtin, 2021, Carnosine, Oxidative and Carbonyl Stress, Antioxidants, and Muscle Fiber Characteristics of Quadriceps Muscle of Patients with COPD, J. Appl. Physiol. source

In the paper

“It is also likely that oxidative stress enhances proteolysis via the calpain and caspase pathways [133], whereas this has not been directly demonstrated in COPD muscle.”

What the sources say

• Supported

  The section on redox signalling during prolonged disuse says oxidative stress could contribute to muscle atrophy by activating proteolytic pathways, including calpain and caspase-3. The citation is attached to that proposed mechanism; the subsequent COPD-specific caveat is the citing authors’ qualification. (LLM, conf=0.91)

  cites [133] Powers, 2010, Reactive Oxygen Species Are Signalling Molecules for Skeletal Muscle Adaptation, Exp. Physiol. source

In the paper

“In the muscle, ROS mainly originate from mitochondrial respiration and membrane (NAPDH oxidase). In the lung, by contrast, ROS are produced by alveolar macrophages and activated neutrophils [117].”

What the sources say

• Partly supported

  Section 3 says skeletal-muscle ROS are mainly produced by the mitochondrial respiratory chain and also identifies NADPH oxidase as a source. Section 8.2 identifies mitochondria and membrane NADPH oxidase as the main sources specifically in respiratory and limb muscles of patients with severe COPD. Our copy does not support the separate claim that lung ROS are produced by alveolar macrophages and activated neutrophils (searched for alveolar macrophages). (LLM, conf=0.86)

  cites [117] Barreiro, E. (2016). Role of Protein Carbonylation in Skeletal Muscle Mass Loss Associated with Chronic Conditions. Proteomes, 4. sourceExperimental — accuracy not yet measured

In the paper

“Oxidative stress is increased both at the systemic and muscular levels in COPD [10,89,116].”

What the sources say

• ?Not checked — no full text of the sourcecites [10] Barreiro, 2016, Molecular and Biological Pathways of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease, Chronic Respir. Dis. source
• Partly supported

  The Abstract Results report increased ROS in quadriceps muscle from patients with COPD, supporting the muscular part of the claim. The Background describes increased oxidative-stress markers in COPD, but does not locate them at the systemic level; the reported measurements are from airway and muscle tissue, not systemic samples. (LLM, conf=0.85)

  cites [89] Haji, 2020, COPDMAP consortium Mitochondrial Dysfunction in Airways and Quadriceps Muscle of Patients with Chronic Obstructive Pulmonary Disease, Respir. Res. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [116] Mano, 2022, Oxidative Stress Causes Muscle Structural Alterations via P38 MAPK Signaling in COPD Mouse Model, J. Bone Miner. Metab. source

In the paper

“Increased lipid peroxidation has also been observed, possibly favored by reduced UCP3 levels [112].”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports reduced UCP3 in COPD muscle and cites observations of an imbalance between oxygen species and antioxidant status. It does not report increased lipid peroxidation, and says whether reduced UCP3 is involved in defence against reactive oxygen species needs further examination. (LLM, conf=0.85)

  cites [112] Gosker, 2003, Uncoupling Protein-3 Content Is Decreased in Peripheral Skeletal Muscle of Patients with COPD, Eur. Respir. J. sourceExperimental — accuracy not yet measured

In the paper

“Ferroptosis, a newly discovered type of cell death resulting from iron-dependent lipid peroxide accumulation, has been reported to be increased both in vitro in CS-exposed C2C12 myotubes and in vivo in a mouse model of COPD [129].”

What the sources say

• Supported

  The Discussion states that chronic cigarette-smoke exposure induced ferroptosis in skeletal muscles of COPD mice and that the finding was recapitulated in C2C12 myotubes exposed to cigarette-smoke extract (CSE). The Abstract Results also reports ferroptosis-related changes in both models. In vitro, the myotubes received CSE rather than cigarette smoke directly. (LLM, conf=0.94)

  cites [129] Zhang, 2022, Myostatin/HIF2α-Mediated Ferroptosis Is Involved in Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease, Int. J. Chronic Obstr. Pulm. Dis. source

In the paper

“For example, increased Mn-superoxide dismutase (SOD) and Cu-Zn-SOD protein levels have been demonstrated in the quadriceps [118,127], whereas unchanged SOD content and decreased SOD activity have been reported in another study [122], and unchanged MnSOD, Cu/ZnSOD, and catalase expressions in cultured COPD myoblasts and myotubes have been found [128].”

What the sources say

• Partly supported

  Split into 3 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 2 not checked. Expand the claim to see per-atom verdicts.

  cites [118] Fermoselle, 2012, Does Oxidative Stress Modulate Limb Muscle Atrophy in Severe COPD Patients?, Eur. Respir. J. sourceExperimental — accuracy not yet measured
• Partly supported

  The Muscle redox balance section (page unavailable) reports higher baseline quadriceps SOD activity in patients with COPD than in controls. It does not report increased protein levels of Mn-SOD or Cu-Zn-SOD, which is the specific finding attributed to this paper. The other findings in the citing sentence have separate citations and are not assessed here. (LLM, conf=0.82)

  cites [127] Barreiro, 2009, Chronic Endurance Exercise Induces Quadriceps Nitrosative Stress in Patients with Severe COPD, Thorax sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [122] Rodriguez, 2012, Muscle and Blood Redox Status after Exercise Training in Severe COPD Patients, Free Radic. Biol. Med. source
• Partly supported

  Split into 3 atoms — 2 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [128] Rodriguez, 2015, Reduced Myotube Diameter, Atrophic Signalling and Elevated Oxidative Stress in Cultured Satellite Cells from COPD Patients, J. Cell. Mol. Med. sourceExperimental — accuracy not yet measured

In the paper

“Mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondria during cell death [115].”

What the sources say

• Supported

  The Background on mPTP Structure identifies the mPTP as the pore responsible for mitochondrial permeability transition (MPT). The Introduction describes MPT as a strategic regulator of cell death and explains its effects on mitochondria, supporting the citing sentence’s broad paraphrase. (LLM, conf=0.91)

  cites [115] Bonora, 2014, The Mitochondrial Permeability Transition Pore and Cancer: Molecular Mechanisms Involved in Cell Death, Front. Oncol. source

In the paper

“Skeletal muscle tissue usually compensates the excessive oxidative stress (induced for example by exercise training) by increasing the levels of antioxidants [122,127], but in COPD, this protective mechanism seems to be defective, although contradictory data have been reported.”

What the sources say

• ?Not checked — no full text of the sourcecites [122] Rodriguez, 2012, Muscle and Blood Redox Status after Exercise Training in Severe COPD Patients, Free Radic. Biol. Med. source
• Partly supported

  The Muscle oxidative stress section reports that exercise increased antioxidant SOD activity in healthy controls but not in patients with severe COPD, supporting a defective exercise-induced response. The Muscle redox balance section also reports higher baseline SOD activity in patients, but the paper does not identify this or other findings as contradictory reports. Its direct evidence is limited to the exercise response studied. (LLM, conf=0.84)

  cites [127] Barreiro, 2009, Chronic Endurance Exercise Induces Quadriceps Nitrosative Stress in Patients with Severe COPD, Thorax sourceExperimental — accuracy not yet measured

In the paper

“Since the early reports of Agusti and colleagues and Gosker and colleagues, who observed, respectively, an increased and unchanged myonuclear fragmentation in muscle cells [111,112]”

What the sources say

• ?Not checked — no full text of the sourcecites [111] Sauleda, 2002, Skeletal Muscle Apoptosis and Weight Loss in Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. source
• ?Could not verify

  The Methods describe muscle-fibre staining and protein measurements, while the Results report fibre types and UCP3 content; neither section reports myonuclear fragmentation. Searches for myonuclear fragmentation and apoptosis-related nuclear measures found no passage addressing whether fragmentation was unchanged in COPD patients. Page numbers were unavailable in our copy. (LLM, conf=0.76)

  cites [112] Gosker, 2003, Uncoupling Protein-3 Content Is Decreased in Peripheral Skeletal Muscle of Patients with COPD, Eur. Respir. J. sourceExperimental — accuracy not yet measured

In the paper

“Surprisingly, few data are available to date in COPD despite the fact that caspase-induced apoptosis is a known contributor of muscle wasting [114].”

What the sources say

• Partly supported

  The Introduction (page unavailable) links muscle wasting and impaired regeneration to TNF and caspase activity. But it describes the relevant caspase activation as non-apoptotic, so it does not establish the cited assertion that caspase-induced apoptosis contributes to muscle wasting. The paper also does not assess how much evidence is available in COPD. (LLM, conf=0.84)

  cites [114] Moresi, V., Garcia-Alvarez, G., Pristerà, A., Rizzuto, E., Albertini, M.C., Rocchi, M., Marazzi, G., Sassoon, D., Adamo, S., and Coletti, D. (2009). Modulation of Caspase Activity Regulates Skeletal Muscle Regeneration and Function in Response to Vasopressin and Tumor Necrosis Factor. PLoS ONE, 4. sourceExperimental — accuracy not yet measured

In the paper

“Later, miR-1, miR-206, and miR-133 were found significantly elevated in the plasma of patients with COPD, as well as miR-499, encoded within the slow myosin heavy chain (MHC) gene and thus promoting type I fibers [156].”

What the sources say

• Supported

  The Results section reports significantly elevated plasma miR-1, miR-206, miR-133 and miR-499 in patients with COPD versus controls. The Introduction says miR-499 is encoded within a slow MHC gene and modulates fibre type; the Discussion describes its role in type I fibre maintenance. Page numbers are not available in the supplied copy. (LLM, conf=0.92)

  cites [156] Donaldson, 2013, Increased Skeletal Muscle-Specific MicroRNA in the Blood of Patients with COPD, Thorax source

In the paper

“Hyperammonemic stress is also known to be associated with COPD, and a recent study evidenced new pathways associated with hyperammonemia in skeletal muscle (in addition to the already-known mitochondrial dysfunction, oxidative stress, and senescence), such as antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation [144].”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [144] Welch, 2021, Integrated Multiomics Analysis Identifies Molecular Landscape Perturbations during Hyperammonemia in Skeletal Muscle and Myotubes, J. Biol. Chem. source

In the paper

“Finally, a recent study evidenced elevated circulating kynurenine levels in COPD patients, as well as reduced muscle levels of kynurenine aminotransferases; this dysregulated kynurenine clearance was attributed to impaired PGC1α signaling [145].”

What the sources say

• Partly supported

  The Results report higher plasma kynurenine and lower muscle KAT4 expression in COPD, but KAT1 and KAT3 were unchanged and KAT2 protein was higher—not a general reduction in kynurenine aminotransferases. The Conclusions suggest impaired muscle PGC1α signaling might be involved; the Discussion says its role in regulating KAT4 remains to be established, so the proposed mechanism is not demonstrated. (LLM, conf=0.90)

  cites [145] Gosker, H.R., Clarke, G., de Theije, C.C., Cryan, J.F., and Schols, A.M.W.J. (2019). Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease. J. Clin. Med., 8. sourceExperimental — accuracy not yet measured

In the paper

“The ubiquitin–proteasome system plays a major role in protein content turnover by degrading misfolded or defective proteins [163,164].”

What the sources say

• Supported

  The Introduction states that the ubiquitin–proteasome system degrades the majority of misfolded or defective cellular proteins and describes its substrate-specific protein degradation mechanism. This supports the claim that it plays a major role in protein turnover through that degradation. (LLM, conf=0.94)

  cites [163] Kitajima, 2020, The Ubiquitin–Proteasome System in Regulation of the Skeletal Muscle Homeostasis and Atrophy: From Basic Science to Disorders, J. Physiol. Sci. source
• ?Not checked — no full text of the sourcecites [164] Gavriilidis, 2018, The MTM1–UBQLN2–HSP Complex Mediates Degradation of Misfolded Intermediate Filaments in Skeletal Muscle, Nat. Cell Biol. source

In the paper

“An increase in the maternally imprinted miR-675 was found in the quadriceps of COPD patients with a low fat-free mass index (FFMI), and this was associated with an inhibition of myoblast proliferation in vitro [159].”

What the sources say

• Supported

  The Introduction identifies miR-675 as arising from maternally expressed H19. The Results (Muscle array validation) report higher quadriceps miR-675 in COPD patients with low FFMI and an inverse correlation with FFMI; the Results (Altered regeneration in low FFMI patients) state that miR-675 inhibited C2C12 cell proliferation in vitro. The paper does not establish that elevated miR-675 caused reduced proliferation in the patients themselves. (LLM, conf=0.91)

  cites [159] Lewis, 2016, Increased Expression of H19/MiR-675 Is Associated with a Low Fat-Free Mass Index in Patients with COPD, J. Cachexia Sarcopenia Muscle source

In the paper

“Of note, the study of Adami and colleagues identified an SNP in the same gene, that was close to be significantly associated with muscle aerobic capacity response [140].”

What the sources say

• Partly supported

  The Results report that rs24575771 within SLC22A3 approached nominal significance (P = 0.058) for association with muscle oxidative capacity, measured by the recovery rate constant k. The study did not test response to training; the Abstract says the candidate SNPs had previously been associated with changes in aerobic capacity following training. (LLM, conf=0.87)

  cites [140] Adami, 2018, Genetic Variants Predicting Aerobic Capacity Response to Training Are Also Associated with Skeletal Muscle Oxidative Capacity in Moderate-to-Severe COPD, Physiol. Genom. sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, levels of miR-499 were associated with nuclear NF-κB p50 in mild/moderate COPD, whereas in severe and very severe disease, miR-206 and miR-133 were associated with circulating cytokines, emphasizing the link with inflammation.”

What the sources say

• Supported

  The Results section, “Plasma miR-499 with markers of inflammation” (page not provided), reports a correlation between miR-499 and nuclear NFκB p50 in GOLD I/II COPD and associations between plasma miR-206 and miR-133 and circulating cytokines, particularly in GOLD III/IV disease. The Discussion, “Disease process and mechanism” (page not provided), links these findings to a possible role for inflammation while retaining uncertainty about the mechanism. (LLM, conf=0.93)

  cites [156] Donaldson, 2013, Increased Skeletal Muscle-Specific MicroRNA in the Blood of Patients with COPD, Thorax source

In the paper

“Among them, one SNPs was located in the DEPTOR gene, of particular interest as it is associated with the regulation of the contractile properties of glycolytic muscles [151].”

What the sources say

• Partly supported

  The paper reports that Deptor is enriched in glycolytic muscles and mediates BAF60c-driven AKT activation and glycolytic metabolism (Abstract; page unavailable). It attributes the observed contractile changes to BAF60c, but does not establish that Deptor itself regulates contractile properties. The COPD SNP finding is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.84)

  cites [151] Meng, 2013, BAF60c Drives Glycolytic Muscle Formation and Improves Glucose Homeostasis through Deptor-Mediated AKT Activation, Nat. Med. sourceExperimental — accuracy not yet measured

In the paper

“miR-1 is also associated with insulin-like growth factor-1 (IGF-1) regulation, providing a possible explanation for reduced protein synthesis (cf. infra).”

What the sources say

• Partly supported

  The Results (Reduced expression of targets of miR-1 in patients with COPD; page unavailable) report increased IGF-1 mRNA and an inverse association between miR-1 and Akt phosphorylation, supporting a link to IGF-1 regulation. The Discussion (miR-1 in muscle biology; page unavailable) raises synthetic resistance as a possible explanation for increased hypertrophy signalling despite muscle wasting, but does not establish that miR-1 regulation explains reduced protein synthesis. (LLM, conf=0.84)

  cites [155] Lewis, 2012, Downregulation of the Serum Response Factor/MiR-1 Axis in the Quadriceps of Patients with COPD, Thorax sourceExperimental — accuracy not yet measured

In the paper

“Later, Adami and colleagues investigated the association between the same SNPs and the muscle oxygen consumption recovery rate constant (k), assessed with near infrared spectroscopy, which reflects skeletal muscle oxidative capacity. Although no significant association was evidenced in COPD patients, three SNPs were associated with k specifically in moderate-to-severe COPD patients [140].”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [140] Adami, 2018, Genetic Variants Predicting Aerobic Capacity Response to Training Are Also Associated with Skeletal Muscle Oxidative Capacity in Moderate-to-Severe COPD, Physiol. Genom. sourceExperimental — accuracy not yet measured

In the paper

“The pioneer study in the matter was conducted by Lewis and colleagues and showed a decreased expression of miR-1 in COPD quadriceps, as well as an increase in its target, histone deacetylase 4 (HDCA4) at the protein level [155].”

What the sources say

• Supported

  The Results section on miRNA expression in quadriceps reports lower miR-1 expression in patients with COPD than in controls. The Results section on miR-1 targets reports higher HDAC4 protein in patients, while identifying HDAC4 as a miR-1 target. Page numbers were not provided in the supplied passages. (LLM, conf=0.94)

  cites [155] Lewis, 2012, Downregulation of the Serum Response Factor/MiR-1 Axis in the Quadriceps of Patients with COPD, Thorax source

In the paper

“Among them, miRNAs represent a growing body of interest in COPD, and they have been associated with several features of the disease in the lung [154].”

What the sources say

• Supported

  The Introduction says the review covers miRNAs in several aspects of COPD pathogenesis, including inflammation, emphysema, tissue repair and lung function. The Differential miRNA expression in COPD section reports altered miRNA expression in lung tissue from patients with COPD and associations with disease stage and impaired lung function. (LLM, conf=0.93)

  cites [154] Osei, 2015, Unravelling the Complexity of COPD by MicroRNAs: It’s a Small World after All, Eur. Respir. J. source

In the paper

“Of note, some studies have failed to report a significant difference between COPD patients and healthy subjects [166], possibly due to the timing of the assessment.”

What the sources say

• Partly supported

  The Results report no significant difference in MuRF-1 protein between COPD patients and controls, but atrogin-1 protein was significantly lower in the COPD group. The Discussion considers measurement timing as a possible reason ubiquitin-ligase levels may not be elevated in stable patients; it does not establish timing as the cause of the MuRF-1 result. Thus the claim is supported for MuRF-1, not for both atrogenes. (LLM, conf=0.89)

  cites [166] Natanek, 2013, MuRF-1 and Atrogin-1 Protein Expression and Quadriceps Fiber Size and Muscle Mass in Stable Patients with COPD, COPD sourceExperimental — accuracy not yet measured

In the paper

“To our knowledge, only one study has investigated the calpain expression in COPD quadriceps and reported an unchanged expression compared to that of the control group [187].”

What the sources say

• Supported

  The Muscle biopsy analysis section says the study measured calpain-3 in quadriceps samples. Table 2 (indexed under Discussion; page not supplied) reports similar baseline calpain-3 protein expression in healthy controls (0.50) and patients with COPD (0.52), with no significant difference marked. The claim that this was the only study is framed as the citing authors’ knowledge, not a finding attributed to this paper. (LLM, conf=0.91)

  cites [187] Constantin, 2013, Skeletal Muscle Molecular Responses to Resistance Training and Dietary Supplementation in COPD, Thorax source

In the paper

“However, a recent clinical trial using a monoclonal antibody blocking its receptor has not shown potent results in treating skeletal muscle wasting for COPD patients [177], despite promising results previously obtained in cancer models [178].”

What the sources say

• Partly supported

  The Abstract identifies bimagrumab as a monoclonal antibody blocking activin type II receptors, and the Results report no significant improvement in walking distance or most measures of muscle strength and mobility. But the Abstract and Discussion report substantial gains in thigh muscle volume and lean body mass, so the trial did show a benefit for muscle wasting, though not for functional performance. The cancer-model claim carries a separate citation and is not assessed here. (LLM, conf=0.88)

  cites [177] Polkey, 2019, Activin Type II Receptor Blockade for Treatment of Muscle Depletion in Chronic Obstructive Pulmonary Disease. A Randomized Trial, Am. J. Respir. Crit. Care Med. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [178] Murphy, 2011, Antibody-Directed Myostatin Inhibition Enhances Muscle Mass and Function in Tumor-Bearing Mice, Am. J. Physiol. Regul. Integr. Comp. Physiol. source

In the paper

“Its expression is increased in the quadriceps of COPD patients [176], possibly related to hypoxia [72].”

What the sources say

• Partly supported

  In “Quadriceps myostatin expression in COPD” (page unavailable), the paper reports increased quadriceps myostatin expression in some COPD patients with low strength, exercise capacity, or physical activity—not in COPD patients generally. The hypoxia explanation is attached to a different citation [72] and is not judged here. (LLM, conf=0.88)

  cites [176] Man, 2010, Quadriceps Myostatin Expression in COPD, Eur. Respir. J. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [72] Hayot, 2011, Myostatin Up-Regulation Is Associated with the Skeletal Muscle Response to Hypoxic Stimuli, Mol. Cell. Endocrinol. source

In the paper

“It is already established that autophagy is increased in the lungs of COPD patients [180].”

What the sources say

• Supported

  The Results section, “Increased autophagy in human COPD lung tissues,” reports significantly increased autophagy-related proteins and markedly more autophagic vacuoles in COPD lung tissue than in controls. This directly supports the citing sentence. (LLM, conf=0.94)

  cites [180] Chen, Z.-H., Kim, H.P., Sciurba, F.C., Lee, S.-J., Feghali-Bostwick, C., Stolz, D.B., Dhir, R., Landreneau, R.J., Schuchert, M.J., and Yousem, S.A. (2008). Egr-1 Regulates Autophagy in Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease. PLoS ONE, 3. source

In the paper

“Nedd4, another muscle-specific E3-ubiquitin ligase acting through Notch1 signaling [167], has recently drawn attention because of its implication in denervation-induced muscle atrophy [168], here unrelated to Notch1 activation.”

What the sources say

• ?Not checked — no full text of the sourcecites [167] Koncarevic, 2006, The Ubiquitin-Protein Ligase Nedd4 Targets Notch1 in Skeletal Muscle and Distinguishes the Subset of Atrophies Caused by Reduced Muscle Tension, FASEB J. source
• Partly supported

  The Discussion reports that deleting Nedd4-1 from skeletal muscle protected mice from early denervation-induced atrophy. It also says the authors found no evidence that Nedd4-1 engages Notch-1 to mediate that atrophy. Calling the mechanism definitively unrelated to Notch-1 activation is stronger than the paper’s qualified conclusion. (LLM, conf=0.86)

  cites [168] Nagpal, P., Plant, P.J., Correa, J., Bain, A., Takeda, M., Kawabe, H., Rotin, D., Bain, J.R., and Batt, J.A.E. (2012). The Ubiquitin Ligase Nedd4-1 Participates in Denervation-Induced Skeletal Muscle Atrophy in Mice. PLoS ONE, 7. sourceExperimental — accuracy not yet measured

In the paper

“In COPD, increased proteolysis is mainly mediated by an overactivation of the ubiquitin (26S)–proteasome system, activated via the muscle-specific E3-ubiquitin ligases Atrogin-1/MAFbx and TRIM63/MuRF-1, also named atrogenes, which are increased in COPD quadriceps [118,165].”

What the sources say

• Partly supported

  The Ubiquitin-proteasome system section reports greater protein ubiquitination and atrogin-1 in the vastus lateralis of muscle-wasted COPD patients, supporting part of the claim. It explicitly reports that MuRF-1 did not differ between study groups; the discussion describes the system's role in severe COPD muscle atrophy as likely rather than establishing that increased proteolysis is mainly mediated by its overactivation. (LLM, conf=0.90)

  cites [118] Fermoselle, 2012, Does Oxidative Stress Modulate Limb Muscle Atrophy in Severe COPD Patients?, Eur. Respir. J. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [165] Doucet, 2007, Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. source

In the paper

“Myostatin is a ligand of the TGF-β pathway in skeletal muscle and a well-known negative regulator of muscle mass, as it inhibits satellite cells’ proliferation and differentiation [174].”

What the sources say

• ?Could not verify

  The opening passage reports that TGF-β inhibits differentiation in cultured myoblasts without affecting their proliferation; the Discussion likewise concerns TGF-β, not myostatin. Searches for myostatin, satellite cells, and muscle mass found no passage addressing the claim about myostatin. The proliferation finding for TGF-β does not establish what myostatin does. (LLM, conf=0.76)

  cites [174] Liu, 2001, TGF-Beta Inhibits Muscle Differentiation through Functional Repression of Myogenic Transcription Factors by Smad3, Genes Dev. sourceExperimental — accuracy not yet measured

In the paper

“However, experimental models do not reflect the complexity of human disease, as currently illustrated in the field of cancer research [190], and are quite heterogeneous in their ability to reproduce every characteristic of COPD sarcopenia.”

What the sources say

• Supported

  The Discussion section, under “General issues in cancer cachexia research and clinical trials,” says no animal model can reflect all contributing factors in human cancer cachexia or simulate its complex biology. This supports the cited cancer-research illustration; the subsequent COPD-sarcopenia clause is the citing authors’ application, not a finding attributed to this source. (LLM, conf=0.92)

  cites [190] Mueller, T.C., Bachmann, J., Prokopchuk, O., Friess, H., and Martignoni, M.E. (2016). Molecular Pathways Leading to Loss of Skeletal Muscle Mass in Cancer Cachexia—Can Findings from Animal Models Be Translated to Humans?. BMC Cancer, 16. source

In the paper

“Classically, circulating TNF-α is reported to be higher in COPD patients than controls and negatively correlated to lean mass [23,24]”

What the sources say

• ?Not checked — no full text of the sourcecites [23] Kochetkova, 2016, 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. source
• ?Not checked — no full text of the sourcecites [24] Wouters, 2002, Systemic Effects in COPD, Chest source

In the paper

“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 [54].”

What the sources say

• ?Not checked — no full text of the sourcecites [54] Liu, 2015, The Role of Interleukin 15 in Protein Degradation in Skeletal Muscles in Rats of Chronic Obstructive Pulmonary Disease, Int. J. Clin. Exp. Med.

In the paper

“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) [42].”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Tang, 2013, Impaired Exercise Capacity and Skeletal Muscle Function in a Mouse Model of Pulmonary Inflammation, J. Appl. Physiol. source

In the paper

“Other known histological alterations include a decreased capillarity, with both a decrease in capillaries density as well as in the capillary-to-fiber ratio [13]”

What the sources say

• ?Not checked — no full text of the sourcecites [13] Jobin, 1998, Chronic Obstructive Pulmonary Disease: Capillarity and Fiber-Type Characteristics of Skeletal Muscle, J. Cardiopulm. Rehabil. Prev. source

In the paper

“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 [49,50].”

What the sources say

• ?Not checked — no full text of the sourcecites [49] 2004, P38 MAPK-Induced Nuclear Factor-KappaB Activity Is Required for Skeletal Muscle Differentiation: Role of Interleukin-6, Mol. Biol. Cell source
• ?Not checked — no full text of the sourcecites [50] Serrano, 2008, Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle Hypertrophy, Cell Metab. source

In the paper

“CD34+ muscle stem cells are specifically affected by hypoxia: Pagé and colleagues found a worse outcome for CD34−/− mice exposed to hypoxia compared to wild-type littermates, with a lower number of fibro-adipogenic progenitors in CD34−/− mice and a greater muscle atrophy as well as a worse functional impairment of the extensor digitorum longus muscle [68].”

What the sources say

• ?Not checked — no full text of the sourcecites [68] Maheux, 2019, CD34 Regulates the Skeletal Muscle Response to Hypoxia, J. Muscle Res. Cell Motil. source

In the paper

“Chronic hypoxia in healthy subjects (implicated in altitude expeditions) induces a loss of muscle mass and decreased fibers’ CSA and mitochondrial density, without affecting the capillary network [65].”

What the sources say

• ?Not checked — no full text of the sourcecites [65] Hoppeler, 1990, Morphological Adaptations of Human Skeletal Muscle to Chronic Hypoxia, Int. J. Sport. Med. source

In the paper

“First, Picard and colleagues observed a decreased state 2 and state 3 respiration in COPD fibers compared to healthy controls. However, a normalization with respect to the citrate synthase activity abolished these differences [98].”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Picard, 2008, The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease: Disuse or Dysfunction?, Am. J. Respir. Crit. Care Med. source

In the paper

“The current knowledge considers that state 3 respiration (ADP-stimulated) is impaired in COPD patients; however, contradictory data are reported regarding complex I- (CI) or complex II-, succinate dehydrogenase (CII-SDH), driven respiration states [100].”

What the sources say

• ?Not checked — no full text of the sourcecites [100] Meyer, 2013, Skeletal Muscle Mitochondrial Dysfunction during Chronic Obstructive Pulmonary Disease: Central Actor and Therapeutic Target, Exp. Physiol. source

In the paper

“no specific and efficient pharmaceutic therapy is available to date, and pulmonary rehabilitation remains the only validated treatment [9].”

What the sources say

• ?Not checked — no full text of the sourcecites [9] Spruit, 2013, An Official American Thoracic Society/European Respiratory Society Statement: Key Concepts and Advances in Pulmonary Rehabilitation, Am. J. Respir. Crit. Care Med. source

In the paper

“Finally, the same team performed a similar study in COPD patients according to their inflammatory status and found an increase in BNIP3 at the protein level in COPD patients with high circulating C-reactive protein (CRP) compared to other COPD patients, pointing out that mitophagy was associated with systemic inflammation [110].”

What the sources say

• ?Not checked — no full text of the sourcecites [110] Gosker, 2018, Systemic Inflammation Is Associated with Mitophagy Signalling in Skeletal Muscle of COPD Patients, Eur. Respir. J. source

In the paper

“Of note, mitochondrial respiration can be affected by external factors, such as glucocorticoid use [105]”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Liu, 2016, Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling, Mol. Pharm. source

In the paper

“The same authors simultaneously investigated COPD patients’ quadriceps biopsies and found decreased FUNDC1 and PINK1 at the protein level, whereas Parkin was increased. Moreover, no change was observed at the mRNA level [109].”

What the sources say

• ?Not checked — no full text of the sourcecites [109] Leermakers, 2016, Peripheral Muscle Mitophagy Is Enhanced in Patients with COPD, Eur. Respir. J. source

In the paper

“The first study was performed in a murine model of lung injury (induced by LPS instillation) and showed an enhanced transcription of mitophagy-related genes such as BNIP3L and PARKIN and a decrease of FUNDC1 [108].”

What the sources say

• ?Not checked — no full text of the sourcecites [108] Leermakers, 2016, Activation of Skeletal Muscle Mitophagy in a Murine Model of Pulmonary and Systemic Inflammation, Eur. Respir. J. source

In the paper

“However, other observations tend to show that metabolic and contractile properties are controlled by distinct signaling pathways [103].”

What the sources say

• ?Not checked — no full text of the sourcecites [103] Schiaffino, 2011, Fiber Types in Mammalian Skeletal Muscles, Physiol. Rev. source

In the paper

“Overall, hypoxia is an important contributor of muscle wasting, although direct mechanistic evidence in COPD muscle is lacking.”

In the paper

“The authors concluded that CIII was the main site of ROS production in COPD skeletal muscle and attributed this to the absence of matrix antioxidant in close vicinity (contrary to complex I).”

What the sources say

• ?Not checked — no full text of the sourcecites [85] Tejedor, 2012, Site of Mitochondrial Reactive Oxygen Species Production in Skeletal Muscle of Chronic Obstructive Pulmonary Disease and Its Relationship with Exercise Oxidative Stress, Am. J. Respir. Cell Mol. Biol. source

In the paper

“Of note, some studies report no difference in oxidative stress markers between COPD patients and healthy smokers [130], implying that oxidative stress could mainly be attributed to CS extracts and not the specificity of systemic involvement of COPD.”

What the sources say

• ?Not checked — no full text of the sourcecites [130] Barreiro, 2010, ENIGMA in COPD Project Cigarette Smoke-Induced Oxidative Stress: A Role in Chronic Obstructive Pulmonary Disease Skeletal Muscle Dysfunction, Am. J. Respir. Crit. Care Med. source

In the paper

“Picard and colleagues reported that there was more resistance to Ca2+-induced mPTP opening in permeabilized muscle fibers from COPD patients than in those from healthy control subjects, attributed to the increased proportion of type II fibers, which are intrinsically more resistant to Ca2+-induced mPTP opening [98].”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Picard, 2008, The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease: Disuse or Dysfunction?, Am. J. Respir. Crit. Care Med. source

In the paper

“only one study reported increased terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL)-positive cells in quadriceps and diaphragm muscles [113]. However, no ultrastructural difference in apoptotic nuclei was noticed.”

What the sources say

• ?Not checked — no full text of the sourcecites [113] Barreiro, 2011, Inflammatory Cells and Apoptosis in Respiratory and Limb Muscles of Patients with COPD, J. Appl. Physiol. source

In the paper

“Discrepancies might also come from the fact that Agusti and colleagues reported an increased apoptosis specifically in COPD patients with low BMI, whereas Gosker and colleagues investigated moderate-to-severe COPD patients without weight indication, and Barreiro and colleagues reported COPD patients with normal body composition.”

In the paper

“Recently, miR542-3p/5p has been found elevated in COPD quadriceps. In vitro data showed its implication in mitochondrial stress and transforming growth factor beta (TGF-β) canonical signaling, and an in vivo experimental study confirmed its role in muscle wasting through a decrease of mitochondrial function [160].”

What the sources say

• ?Not checked — no full text of the sourcecites [160] Garros, 2017, MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-Acquired Weakness, Am. J. Respir. Crit. Care Med. source

In the paper

“Epigenetic modifications, whether methylation, acetylation, or muscle-specific micro-RNAs (myomiRNAs) play essential roles in muscle physiology, including embryogenesis and adaptation to environmental factors (for a comprehensive review, see [152]).”

What the sources say

• ?Not checked — no full text of the sourcecites [152] Barreiro, 2013, Epigenetic Regulation of Muscle Phenotype and Adaptation: A Potential Role in COPD Muscle Dysfunction, J. Appl. Physiol. source

In the paper

“These discrepancies are possibly explained by the absence of matching for smoking and physical activity in the first study. Differences in timing of miRNA secretion can also be invoked.”

In the paper

“All mechanisms detailed above converge to deleterious consequences on muscle mass regulation, destabilizing the atrophy/hypertrophy balance.”

In the paper

“Willis-Owen and colleagues also reported an increase of FST, encoding follistatin, a propeptide inhibiting myostatin signaling and promoting myogenic differentiation. Thus, this upregulation might represent a compensatory mechanism.”

In the paper

“Maternally imprinted genes are usually associated with limiting growth, whereas paternal genes bear the reverse effect [158].”

What the sources say

• ?Not checked — no full text of the sourcecites [158] Kemp, 2017, Epigenetics and Susceptibility to Muscle Wasting in COPD, Arch. Bronconeumol. source

In the paper

“Among them, two genes were confirmed as in vitro modifiers of muscle mass, as their silencing with RNA interference increased the length of myotubes.”

What the sources say

• ?Not checked — no full text of the sourcecites [148] Gonzales, 2019, Genome-Wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2, Am. J. Hum. Genet. source

In the paper

“However, patients and controls were not matched for physical activity, unravelling a well-known bias due to deconditioning in COPD patients.”

In the paper

“Furthermore, in 2010, a study conducted by Timmons and colleagues identified 11 single-nucleotide polymorphisms (SNPs) associated with the increase in maximal oxygen uptake (VO2max) after exercise training in the general population [150].”

What the sources say

• ?Not checked — no full text of the sourcecites [150] Timmons, 2010, Using Molecular Classification to Predict Gains in Maximal Aerobic Capacity Following Endurance Exercise Training in Humans, J. Appl. Physiol. source

In the paper

“Epigenetic modifications are believed to control muscle fiber type, and can be influenced by external factors such as nutrition [153].”

What the sources say

• ?Not checked — no full text of the sourcecites [153] Baar, 2010, Epigenetic Control of Skeletal Muscle Fibre Type, Acta Physiol. source

In the paper

“These results point towards an impairment of the muscle energy production and are consistent with other studies showing low baseline creatine kinase and ATP concentrations [121].”

What the sources say

• ?Not checked — no full text of the sourcecites [121] Barreiro, 2005, Expression and Carbonylation of Creatine Kinase in the Quadriceps Femoris Muscles of Patients with Chronic Obstructive Pulmonary Disease, Am. J. Respir. Cell Mol. Biol. source

In the paper

“However, in that study, although the authors performed muscular biopsies, they did not investigate the level of miRNA in the quadriceps, which would have allowed them to perform correlations with plasma levels.”

In the paper

“More recently, Balnis and colleagues showed in satellite cells a defective autophagic flux associated with important proteins’ upregulation such as Beclin-1. In that work, autophagy seemed to be correlated to satellite cell dysfunction contributing to the pathogenesis of emphysema in a transgenic mouse model [185].”

What the sources say

• ?Not checked — no full text of the sourcecites [185] Balnis, 2022, Deaccelerated Myogenesis and Autophagy in Genetically Induced Pulmonary Emphysema, Am. J. Respir. Cell Mol. Biol. source

In the paper

“In the quadriceps of exacerbating COPD patients, IGF-1 was found downregulated at the mRNA level, as well as myoD at the protein level [28].”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Crul, 2007, Markers of Inflammation and Disuse in Vastus Lateralis of Chronic Obstructive Pulmonary Disease Patients, Eur. J. Clin. Investig. source

In the paper

“However, that study lacked the assessment of the LC3BII/LC3BI ratio (reflecting the active form) as well as that of other autophagy markers.”

In the paper

“Yet, its expression has not been thoroughly investigated in COPD, with only one report indicating an increased expression in COPD quadriceps [169].”

What the sources say

• ?Not checked — no full text of the sourcecites [169] Plant, 2010, Cellular Markers of Muscle Atrophy in Chronic Obstructive Pulmonary Disease, Am. J. Respir. Cell Mol. Biol. source

In the paper

“Of note, this study was not conducted on the same patients (exacerbating versus stable COPD patients).”

In the paper

“These discrepancies might come from the diversity in patients’ recruitment and warrant further investigations, although once again, the timing of the investigation is probably the most crucial point.”

In the paper

“Puig-Vilanova and colleagues reported an increase in p38-MAPK levels in COPD quadriceps but an unchanged ERK1/2 expression [123].”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Rodriguez, 2015, Oxidative Stress, Redox Signaling Pathways, and Autophagy in Cachectic Muscles of Male Patients with Advanced COPD and Lung Cancer, Free Radic. Biol. Med. source

In the paper

“Upon binding to its receptor, the activin receptor type II A/B, it activates catabolic pathways via the phosphorylation of downstream effectors Smad2/3 and simultaneously inhibits anabolic pathways [175].”

What the sources say

• ?Not checked — no full text of the sourcecites [175] Morissette, 2009, Myostatin Inhibits IGF-I-Induced Myotube Hypertrophy through Akt, Am. J. Physiol. Cell Physiol. source

In the paper

“In skeletal muscle, protein synthesis is mainly mediated by the IGF/Akt/mTOR pathway, which seems globally decreased, although contradictory data between mRNA and protein levels of different components of the cascade have been reported.”

In the paper

“A major other proteolytic pathway is autophagy-induced lysosomal degradation, an essential process leading to the degradation of cytoplasmic portions of variable sizes in the lysosomes (see the review by [179]).”

What the sources say

• ?Not checked — no full text of the sourcecites [179] Hussain, 2013, Role of Autophagy in COPD Skeletal Muscle Dysfunction, J. Appl. Physiol. source

In the paper

“It also seems to play an essential role in skeletal muscle wasting, as muscle-autophagy-deficient mice (muscle-specific deletion of Atg7) exhibit sarcopenia features [181].”

What the sources say

• ?Not checked — no full text of the sourcecites [181] Masiero, 2009, Autophagy Is Required to Maintain Muscle Mass, Cell Metab. source

In the paper

“Although conflicting results have been reported, the global conclusion is that autophagy is enhanced in COPD locomotor muscles.”

In the paper

“For example, a study performed on the quadriceps of 91 COPD patients showed that Akt phosphorylation was decreased in COPD compared to healthy subjects as well as in sarcopenic versus nonsarcopenic patients. However, other markers of protein synthesis signaling such as S6- or 4EBP1-phosphorylations were increased in both cases [188].”

What the sources say

• ?Not checked — no full text of the sourcecites [188] Kneppers, 2016, Impaired Coordination of Skeletal Muscle Protein Turnover Signalling in Sarcopenic COPD Patients, Eur. Respir. J. source

In the paper

“Discrepancies between studies might come from the complex interconnection between pathways, as well as the patients’ selection and the fact that biopsies are taken at different time courses of the disease.”

In the paper

“In this regard, experimental models can help study every stage of muscle wasting, provided that their functional and histological characteristics fit those of the disease.”

In the paper

“Skeletal muscle wasting is a crucial issue for COPD patients, both associated with an impaired quality of life and a significant mortality.”

In the paper

“Indeed, skeletal muscle tissue alterations in rodent models are inconsistent, partly due to the diversity of the experimental procedures used (CS exposure, elastase or lipopolysaccharide instillations, transgenic models, etc.).”

In the paper

“The underlying pathophysiology is vastly multifactorial and implies both extrinsic and intrinsic factors.”