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

May combine two claims.

Some authors have found increased COX activity in COPD patients with resting hypoxemia and with exercise hypoxemia, while others have not found any significant increase.

“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].”

• cites [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. sourceNot checked — no full text of the source
• cites [97] Godoy, 2009, Abnormal Mitochondrial Function in Locomotor and Respiratory Muscles of COPD Patients, Eur. Respir. J. sourceDisputed

  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.

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

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

COPD is now considered as a systemic inflammatory disease implicating a wide range of cytokines and chemokines and including several comorbidities.

“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.”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Structural alterations of peripheral skeletal muscle in COPD include a global muscle atrophy with loss in number and size of muscle fibers, reflected by decreased thigh diameter and decreased fibers' cross-sectional area.

“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]”

• cites [11] Bernard, 1998, Peripheral Muscle Weakness in Patients with Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. sourceNot checked — no full text of the source
• 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. sourceSupported

May combine two claims.

In the quadriceps of COPD patients, muscular TNF-α levels have been reported as significantly elevated, decreased, and unaltered, or even undetected at the protein level.

“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]”

• cites [27] Barreiro, 2008, Cytokine Profile in Quadriceps Muscles of Patients with Severe COPD, Thorax sourceSupported
• cites [28] Crul, 2007, Markers of Inflammation and Disuse in Vastus Lateralis of Chronic Obstructive Pulmonary Disease Patients, Eur. J. Clin. Investig. sourceNot checked — no full text of the source
• cites [29] Torres, 2005, Skeletal Muscle Inflammation and Nitric Oxide in Patients with COPD, Eur. Respir. J. sourceSupported
• cites [30] Koechlin, 2005, Hypoxaemia Enhances Peripheral Muscle Oxidative Stress in Chronic Obstructive Pulmonary Disease, Thorax sourceSupported
• cites [31] Remels, 2010, TNF-α Impairs Regulation of Muscle Oxidative Phenotype: Implications for Cachexia?, FASEB J. sourceCould 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)

  Experimental — accuracy not yet measured

May combine two claims.

Circulating IL-6 is elevated in COPD patients compared to healthy subjects, both during and outside exacerbations, and is associated with reduced quadriceps strength.

“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].”

• cites [44] Sin, 2008, Interleukin-6: A Red Herring or a Real Catch in COPD?, Chest sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [45] Yende, 2006, Inflammatory Markers Are Associated with Ventilatory Limitation and Muscle Dysfunction in Obstructive Lung Disease in Well Functioning Elderly Subjects, Thorax sourceSupported

May combine two claims.

Chronic, low-grade inflammation induces muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secretome, whereas acute inflammation activates anabolic pathways leading to muscle regeneration.

“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.”

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

May combine two claims.

HDAC2 level is decreased in the quadriceps of COPD patients, associated with an increase in the NF-κB pathway.

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

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

May combine two claims.

In myocytes, binding of TNF-α to its receptor TNF-R activates the p38-MAPK pathway, leading to silencing of target genes such as Pax7 and Notch1, promoting satellite cell differentiation into myotubes.

“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]”

• cites [39] Tidball, 2017, Regulation of Muscle Growth and Regeneration by the Immune System, Nat. Rev. Immunol. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Inflammation is not the sole driver of COPD muscle atrophy, as exercise can affect factors regulating muscle hypertrophy and regeneration without affecting levels of systemic or local muscle inflammation.

“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].”

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

May combine two claims.

HIF1α and its downstream target VEGF were found elevated in quadriceps biopsies of COPD patients and correlated to the level of muscular TNF-α.

“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.”

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

May combine two claims.

Therapies against TNF-α have not proven effective for outcomes such as dyspnea or exacerbations, suggesting that TNF-α is not the primary or at least the sole driver of COPD inflammation.

“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.”

• cites [43] Aaron, 2013, TNFα Antagonists for Acute Exacerbations of COPD: A Randomised Double-Blind Controlled Trial, Thorax sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Transgenic mice chronically overexpressing IL-6 exhibit marked muscle atrophy, but knockout of IL-6 was not sufficient to prevent sarcopenia in a sepsis mouse model.

“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].”

• cites [47] Tsujinaka, 1996, Interleukin 6 Receptor Antibody Inhibits Muscle Atrophy and Modulates Proteolytic Systems in Interleukin 6 Transgenic Mice, J. Clin. Investig. sourceSupported
• cites [48] Williams, 1998, Sepsis in Mice Stimulates Muscle Proteolysis in the Absence of IL-6, Am. J. Physiol. sourceNot checked — no full text of the source

May combine two claims.

Adipose tissue infiltration has been reported in COPD muscle, particularly in the obese sarcopenic phenotype where adipose inflammation leads to redistribution of fat to the intra-abdominal area and skeletal muscle tissue.

“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]”

• cites [16] Persson, 2022, Skeletal Myosteatosis Is Associated with Systemic Inflammation and a Loss of Muscle Bioenergetics in Stable COPD, J. Inflamm. Res. sourcePartly 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)

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

  Experimental — accuracy not yet measured

May combine two claims.

A mouse model exposed to cigarette smoke exhibited increased circulating TNF-α levels, which were correlated to detrimental outcomes such as muscle mass, decreased capillarization, and increased catabolism.

“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].”

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

May combine two claims.

IFN-γ has been reported as unchanged at the protein level in COPD quadriceps compared to controls, while a recent transcriptional analysis shows a globally downregulated interferon response in COPD quadriceps.

“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].”

• cites [27] Barreiro, 2008, Cytokine Profile in Quadriceps Muscles of Patients with Severe COPD, Thorax sourceSupported
• cites [56] Cano, 2018, Network Modules Uncover Mechanisms of Skeletal Muscle Dysfunction in COPD Patients, J. Transl. Med. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Intermittent hypoxia may play a role in skeletal muscle wasting, driven by mitochondrial dysfunction and lower activity.

“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].”

• cites [84] Attaway, 2022, Adaptive Exhaustion during Prolonged Intermittent Hypoxia Causes Dysregulated Skeletal Muscle Protein Homeostasis, J. Physiol. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Gifford and colleagues confirmed their observations in 2017 on a different cohort of COPD patients matched to healthy controls based on the same physical activity, observing a diminished state 3 CI-driven respiration and a trend to a lower state 3:CI+CII driven respiration.

“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.”

• 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. sourcePartly supported

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

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Gifford and colleagues concluded that the reduction in state 3:CI+CII respiration was largely driven by diminished CI-driven respiration rather than CII-driven respiration.

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

• 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. sourceSupported

May combine two claims.

Mitochondrial function can regulate muscle fiber phenotype in vivo, as transfecting the defective CII subunit C into mouse muscles increased both mitochondrial respiration and oxidative myofiber proportion.

“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.”

• 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. sourceSupported

May combine two claims.

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.

“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].”

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

May combine two claims.

Hypoxia seems to play a prominent role in the skeletal muscle wasting of COPD patients, as suggested by transcriptomic studies evidencing upregulation of four histone deacetylases in the muscle of COPD patients compared to healthy subjects and correlated with oxygen availability.

“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].”

• 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. sourcePartly supported

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

  Experimental — accuracy not yet measured

May combine two claims.

Expressions of electron transport chain complex proteins I, II, III, and V have been reported as unchanged in patients with mild COPD (GOLD II) but decreased in patients with severe or very severe COPD (GOLD III-IV).

“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].”

• cites [89] Haji, 2020, COPDMAP consortium Mitochondrial Dysfunction in Airways and Quadriceps Muscle of Patients with Chronic Obstructive Pulmonary Disease, Respir. Res. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Exercise training improved functional capacity in both normoxemic and hypoxemic COPD patients, but structural improvements (increased mitochondrial density, capillary-to-fiber ratio, and fibers' cross-sectional area) occurred only in normoxemic ones.

“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].”

• cites [80] Costes, 2015, Impaired Exercise Training-Induced Muscle Fiber Hypertrophy and Akt/MTOR Pathway Activation in Hypoxemic Patients with COPD, J. Appl. Physiol. sourcePartly supported

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

  Experimental — accuracy not yet measured

May combine two claims.

Only one study investigated DNML1 expression in COPD quadriceps and found a decreased protein level.

“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].”

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

May combine two claims.

Remels and colleagues observed low levels of PGC1-α and TFAM in COPD quadriceps; these differences were further enhanced in cachectic COPD patients.

“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].”

• cites [90] Remels, 2007, Peroxisome Proliferator-Activated Receptor Expression Is Reduced in Skeletal Muscle in COPD, Eur. Respir. J. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

During COPD exacerbations, mitochondrial respiration appears further decreased, with decreased aspartate catabolism and COX6C activity in quadriceps.

“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].”

• cites [104] Crul, 2010, Gene Expression Profiling in Vastus Lateralis Muscle During an Acute Exacerbation of COPD, Cell. Physiol. Biochem. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Evidence for DNA damage in COPD muscle is scarce but includes higher 8-OHdG levels in COPD quadriceps compared to controls.

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

• 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 sourceSupported

May combine two claims.

Several studies have found increased lipofuscin accumulation in COPD quadriceps and higher levels of 4-HNE in quadriceps tissue, as well as in cultured myotubes from COPD patients.

“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].”

• cites [126] Allaire, 2002, Lipofuscin Accumulation in the Vastus Lateralis Muscle in Patients with Chronic Obstructive Pulmonary Disease, Muscle Nerve sourceNot checked — no full text of the source
• 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 sourceSupported
• cites [127] Barreiro, 2009, Chronic Endurance Exercise Induces Quadriceps Nitrosative Stress in Patients with Severe COPD, Thorax sourceSupported
• cites [128] Rodriguez, 2015, Reduced Myotube Diameter, Atrophic Signalling and Elevated Oxidative Stress in Cultured Satellite Cells from COPD Patients, J. Cell. Mol. Med. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Carnosine is unchanged in the muscle of COPD patients compared to healthy controls, but in COPD patients it is decreased in the quadriceps of GOLD III-IV patients compared to GOLD I-II, despite an increased proportion of type II myofibers.

“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].”

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

May combine two claims.

It is likely that oxidative stress enhances proteolysis via the calpain and caspase pathways, although this has not been directly demonstrated in COPD muscle.

“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.”

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

May combine two claims.

In muscle, ROS mainly originate from mitochondrial respiration and membrane NADPH oxidase; in lung, ROS are produced by alveolar macrophages and activated neutrophils.

“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].”

• cites [117] Barreiro, E. (2016). Role of Protein Carbonylation in Skeletal Muscle Mass Loss Associated with Chronic Conditions. Proteomes, 4. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Oxidative stress is increased both at the systemic and muscular levels in COPD.

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

• cites [10] Barreiro, 2016, Molecular and Biological Pathways of Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease, Chronic Respir. Dis. sourceNot checked — no full text of the source
• cites [89] Haji, 2020, COPDMAP consortium Mitochondrial Dysfunction in Airways and Quadriceps Muscle of Patients with Chronic Obstructive Pulmonary Disease, Respir. Res. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [116] Mano, 2022, Oxidative Stress Causes Muscle Structural Alterations via P38 MAPK Signaling in COPD Mouse Model, J. Bone Miner. Metab. sourceNot checked — no full text of the source

May combine two claims.

Increased lipid peroxidation has been observed in COPD muscle, possibly favored by reduced UCP3 levels.

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

• cites [112] Gosker, 2003, Uncoupling Protein-3 Content Is Decreased in Peripheral Skeletal Muscle of Patients with COPD, Eur. Respir. J. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Ferroptosis is increased both in vitro in CS-exposed C2C12 myotubes and in vivo in a mouse model of COPD.

“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].”

• 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. sourceSupported

May combine two claims.

Increased Mn-superoxide dismutase (SOD) and Cu-Zn-SOD protein levels have been demonstrated in COPD quadriceps, whereas unchanged SOD content and decreased SOD activity have been reported in another study, and unchanged MnSOD, Cu/ZnSOD, and catalase expressions have been found in cultured COPD myoblasts and myotubes.

“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].”

• cites [118] Fermoselle, 2012, Does Oxidative Stress Modulate Limb Muscle Atrophy in Severe COPD Patients?, Eur. Respir. J. sourcePartly 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.

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

  Experimental — accuracy not yet measured
• cites [122] Rodriguez, 2012, Muscle and Blood Redox Status after Exercise Training in Severe COPD Patients, Free Radic. Biol. Med. sourceNot checked — no full text of the source
• cites [128] Rodriguez, 2015, Reduced Myotube Diameter, Atrophic Signalling and Elevated Oxidative Stress in Cultured Satellite Cells from COPD Patients, J. Cell. Mol. Med. sourcePartly supported

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

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondria during cell death.

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

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

May combine two claims.

In COPD, the protective mechanism of increasing antioxidants in response to oxidative stress seems defective, although contradictory data have been reported.

“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.”

• cites [122] Rodriguez, 2012, Muscle and Blood Redox Status after Exercise Training in Severe COPD Patients, Free Radic. Biol. Med. sourceNot checked — no full text of the source
• cites [127] Barreiro, 2009, Chronic Endurance Exercise Induces Quadriceps Nitrosative Stress in Patients with Severe COPD, Thorax sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Agusti and colleagues observed increased myonuclear fragmentation in muscle cells of COPD patients, whereas Gosker and colleagues observed unchanged myonuclear fragmentation.

“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]”

• cites [111] Sauleda, 2002, Skeletal Muscle Apoptosis and Weight Loss in Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. sourceNot checked — no full text of the source
• cites [112] Gosker, 2003, Uncoupling Protein-3 Content Is Decreased in Peripheral Skeletal Muscle of Patients with COPD, Eur. Respir. J. sourceCould 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)

  Experimental — accuracy not yet measured

May combine two claims.

Few data are available on caspase-induced apoptosis in COPD despite caspase-induced apoptosis being a known contributor of muscle wasting.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

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 gene and thus promoting type I fibers.

“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].”

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

May combine two claims.

Hyperammonemic stress is associated with COPD, and a recent study evidenced new pathways associated with hyperammonemia in skeletal muscle, such as antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation.

“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].”

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

May combine two claims.

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.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The ubiquitin-proteasome system plays a major role in protein content turnover by degrading misfolded or defective proteins.

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

• 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. sourceSupported
• cites [164] Gavriilidis, 2018, The MTM1–UBQLN2–HSP Complex Mediates Degradation of Misfolded Intermediate Filaments in Skeletal Muscle, Nat. Cell Biol. sourceNot checked — no full text of the source

May combine two claims.

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.

“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].”

• 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 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

An SNP in SLC22A3 was close to being significantly associated with muscle aerobic capacity response.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

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.

“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.”

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

May combine two claims.

One SNP associated with k in moderate-to-severe COPD patients was located in the DEPTOR gene, which is associated with regulation of contractile properties of glycolytic muscles.

“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].”

• cites [151] Meng, 2013, BAF60c Drives Glycolytic Muscle Formation and Improves Glucose Homeostasis through Deptor-Mediated AKT Activation, Nat. Med. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

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

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

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

  Experimental — accuracy not yet measured

May combine two claims.

Adami and colleagues investigated the association between the same SNPs and the muscle oxygen consumption recovery rate constant (k), assessed with near infrared spectroscopy, reflecting skeletal muscle oxidative capacity; no significant association was evidenced in COPD patients, but three SNPs were associated with k specifically in moderate-to-severe COPD patients.

“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].”

• 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. sourcePartly supported

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

  Experimental — accuracy not yet measured

May combine two claims.

Lewis and colleagues showed decreased expression of miR-1 in COPD quadriceps, as well as an increase in its target histone deacetylase 4 (HDAC4) at the protein level.

“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].”

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

Probably not a substantial claim: may not pass S3 (load-bearing).

miRNAs have been associated with several features of COPD in the lung.

“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].”

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

May combine two claims.

Some studies have failed to report a significant difference in atrogenes between COPD patients and healthy subjects, possibly due to timing of assessment.

“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.”

• cites [166] Natanek, 2013, MuRF-1 and Atrogin-1 Protein Expression and Quadriceps Fiber Size and Muscle Mass in Stable Patients with COPD, COPD sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Only one study has investigated calpain expression in COPD quadriceps and reported an unchanged expression compared to controls.

“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].”

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

May combine two claims.

A recent clinical trial using a monoclonal antibody blocking the myostatin receptor has not shown potent results in treating skeletal muscle wasting for COPD patients, despite promising results previously obtained in cancer models.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [178] Murphy, 2011, Antibody-Directed Myostatin Inhibition Enhances Muscle Mass and Function in Tumor-Bearing Mice, Am. J. Physiol. Regul. Integr. Comp. Physiol. sourceNot checked — no full text of the source

May combine two claims.

Myostatin expression is increased in the quadriceps of COPD patients, possibly related to hypoxia.

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

• cites [176] Man, 2010, Quadriceps Myostatin Expression in COPD, Eur. Respir. J. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [72] Hayot, 2011, Myostatin Up-Regulation Is Associated with the Skeletal Muscle Response to Hypoxic Stimuli, Mol. Cell. Endocrinol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Autophagy is increased in the lungs of COPD patients.

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

• 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. sourceSupported

May combine two claims.

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

“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.”

• cites [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. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

In COPD, increased proteolysis is mainly mediated by overactivation of the ubiquitin (26S)-proteasome system, activated via the muscle-specific E3-ubiquitin ligases Atrogin-1/MAFbx and TRIM63/MuRF-1, which are increased in COPD quadriceps.

“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].”

• cites [118] Fermoselle, 2012, Does Oxidative Stress Modulate Limb Muscle Atrophy in Severe COPD Patients?, Eur. Respir. J. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [165] Doucet, 2007, Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease, Am. J. Respir. Crit. Care Med. sourceNot checked — no full text of the source

May combine two claims.

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.

“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].”

• cites [174] Liu, 2001, TGF-Beta Inhibits Muscle Differentiation through Functional Repression of Myogenic Transcription Factors by Smad3, Genes Dev. sourceCould 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)

  Experimental — accuracy not yet measured

May combine two claims.

Experimental models do not reflect the complexity of human disease, as illustrated in cancer research, and are heterogeneous in their ability to reproduce every characteristic of COPD sarcopenia.

“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.”

• 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. sourceSupported

May combine two claims.

Circulating TNF-α is reported to be higher in COPD patients than controls and negatively correlated to lean mass.

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

• cites [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. sourceNot checked — no full text of the source
• cites [24] Wouters, 2002, Systemic Effects in COPD, Chest sourceNot checked — no full text of the source

May combine two claims.

IL-15 was increased and correlated with TNF-α in a rat model of COPD induced by cigarette smoke exposure and LPS instillations, in serum and in both peripheral and respiratory skeletal muscles.

“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].”

• cites [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.Not checked — no full text of the source

May combine two claims.

Overexpression of TNF-α in the lung leads to increased muscle fatigue, decreased muscle mass and mitochondrial content, and increased catabolism, mostly in male mice.

“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].”

• cites [42] Tang, 2013, Impaired Exercise Capacity and Skeletal Muscle Function in a Mouse Model of Pulmonary Inflammation, J. Appl. Physiol. sourceNot checked — no full text of the source

May combine two claims.

Known histological alterations in COPD muscle include decreased capillarity, with both a decrease in capillary density and in the capillary-to-fiber ratio.

“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]”

• cites [13] Jobin, 1998, Chronic Obstructive Pulmonary Disease: Capillarity and Fiber-Type Characteristics of Skeletal Muscle, J. Cardiopulm. Rehabil. Prev. sourceNot checked — no full text of the source

May combine two claims.

In vitro, IL-6 bears anabolic effects by regulating satellite cells' function and enhancing glucose metabolism; loss of IL-6 signaling in myoblasts results in reduced proliferation and migration.

“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].”

• cites [49] 2004, P38 MAPK-Induced Nuclear Factor-KappaB Activity Is Required for Skeletal Muscle Differentiation: Role of Interleukin-6, Mol. Biol. Cell sourceNot checked — no full text of the source
• cites [50] Serrano, 2008, Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle Hypertrophy, Cell Metab. sourceNot checked — no full text of the source

May combine two claims.

CD34+ muscle stem cells are specifically affected by hypoxia: CD34−/− mice exposed to hypoxia had a worse outcome than wild-type littermates, with greater muscle atrophy and worse functional impairment of the extensor digitorum longus muscle.

“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].”

• cites [68] Maheux, 2019, CD34 Regulates the Skeletal Muscle Response to Hypoxia, J. Muscle Res. Cell Motil. sourceNot checked — no full text of the source

May combine two claims.

Chronic hypoxia in healthy subjects induces a loss of muscle mass and decreased fibers' cross-sectional area and mitochondrial density, without affecting the capillary network.

“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].”

• cites [65] Hoppeler, 1990, Morphological Adaptations of Human Skeletal Muscle to Chronic Hypoxia, Int. J. Sport. Med. sourceNot checked — no full text of the source

May combine two claims.

Picard and colleagues observed decreased state 2 and state 3 respiration in COPD fibers compared to healthy controls; normalization with respect to citrate synthase activity abolished these differences.

“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].”

• cites [98] Picard, 2008, The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease: Disuse or Dysfunction?, Am. J. Respir. Crit. Care Med. sourceNot checked — no full text of the source

May combine two claims.

Current knowledge considers that state 3 respiration (ADP-stimulated) is impaired in COPD patients; however, contradictory data are reported regarding complex I- or complex II-driven respiration states.

“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].”

• cites [100] Meyer, 2013, Skeletal Muscle Mitochondrial Dysfunction during Chronic Obstructive Pulmonary Disease: Central Actor and Therapeutic Target, Exp. Physiol. sourceNot checked — no full text of the source

May combine two claims.

No specific and efficient pharmaceutic therapy is available to date, and pulmonary rehabilitation remains the only validated treatment.

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

• cites [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. sourceNot checked — no full text of the source

May combine two claims.

In COPD patients with high circulating C-reactive protein (CRP), BNIP3 protein level is increased in muscle compared to other COPD patients, indicating mitophagy is associated with systemic inflammation.

“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].”

• cites [110] Gosker, 2018, Systemic Inflammation Is Associated with Mitophagy Signalling in Skeletal Muscle of COPD Patients, Eur. Respir. J. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Mitochondrial respiration can be affected by external factors such as glucocorticoid use.

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

• cites [105] Liu, 2016, Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling, Mol. Pharm. sourceNot checked — no full text of the source

May combine two claims.

In COPD patients' quadriceps biopsies, FUNDC1 and PINK1 are decreased at the protein level, Parkin is increased, and no change is observed at the mRNA level.

“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].”

• cites [109] Leermakers, 2016, Peripheral Muscle Mitophagy Is Enhanced in Patients with COPD, Eur. Respir. J. sourceNot checked — no full text of the source

May combine two claims.

In a murine model of lung injury induced by LPS instillation, transcription of mitophagy-related genes BNIP3L and PARKIN is enhanced and FUNDC1 is decreased.

“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].”

• cites [108] Leermakers, 2016, Activation of Skeletal Muscle Mitophagy in a Murine Model of Pulmonary and Systemic Inflammation, Eur. Respir. J. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Metabolic and contractile properties in muscle may be controlled by distinct signaling pathways.

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

• cites [103] Schiaffino, 2011, Fiber Types in Mammalian Skeletal Muscles, Physiol. Rev. sourceNot checked — no full text of the source

May combine two claims.

Hypoxia is an important contributor of muscle wasting, although direct mechanistic evidence in COPD muscle is lacking.

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

May combine two claims.

CIII is the main site of ROS production in COPD skeletal muscle, attributed to the absence of matrix antioxidant in close vicinity, contrary to complex I.

“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).”

• cites [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. sourceNot checked — no full text of the source

May combine two claims.

Some studies report no difference in oxidative stress markers between COPD patients and healthy smokers, implying that oxidative stress could mainly be attributed to cigarette smoke extracts and not the specificity of systemic involvement of COPD.

“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.”

• cites [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. sourceNot checked — no full text of the source

May combine two claims.

Permeabilized muscle fibers from COPD patients show more resistance to Ca2+-induced mPTP opening than those from healthy controls, attributed to an increased proportion of type II fibers, which are intrinsically more resistant.

“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].”

• cites [98] Picard, 2008, The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease: Disuse or Dysfunction?, Am. J. Respir. Crit. Care Med. sourceNot checked — no full text of the source

May combine two claims.

Only one study has reported increased TUNEL-positive cells in quadriceps and diaphragm muscles of COPD patients, with no ultrastructural difference in apoptotic nuclei.

“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.”

• cites [113] Barreiro, 2011, Inflammatory Cells and Apoptosis in Respiratory and Limb Muscles of Patients with COPD, J. Appl. Physiol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Discrepancies in apoptosis findings may come from differences in patient BMI and body composition: Agusti reported increased apoptosis specifically in COPD patients with low BMI, Gosker investigated moderate-to-severe COPD without weight indication, and Barreiro reported COPD patients with normal body composition.

“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.”

May combine two claims.

miR542-3p/5p has been found elevated in COPD quadriceps; in vitro data showed its implication in mitochondrial stress and TGF-β canonical signaling, and an in vivo experimental study confirmed its role in muscle wasting through a decrease of mitochondrial function.

“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].”

• cites [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. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Epigenetic modifications, whether methylation, acetylation, or muscle-specific micro-RNAs, play essential roles in muscle physiology, including embryogenesis and adaptation to environmental factors.

“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]).”

• cites [152] Barreiro, 2013, Epigenetic Regulation of Muscle Phenotype and Adaptation: A Potential Role in COPD Muscle Dysfunction, J. Appl. Physiol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Discrepancies in miRNA findings are possibly explained by the absence of matching for smoking and physical activity in the first study, and differences in timing of miRNA secretion can also be invoked.

“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.”

May combine two claims.

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

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

• AssumptionRests on an assumption: Muscle protein turnover is impaired in COPD through both enhanced degradation and reduced synthesis.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Maternally imprinted genes are usually associated with limiting growth, whereas paternal genes bear the reverse effect.

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

• cites [158] Kemp, 2017, Epigenetics and Susceptibility to Muscle Wasting in COPD, Arch. Bronconeumol. sourceNot checked — no full text of the source

May combine two claims.

Among these loci, two genes, CPNE1 and STC2, were confirmed as in vitro modifiers of muscle mass, as their silencing with RNA interference increased the length of myotubes.

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

• cites [148] Gonzales, 2019, Genome-Wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2, Am. J. Hum. Genet. sourceNot checked — no full text of the source

May combine two claims.

Patients and controls in the FST study were not matched for physical activity, introducing a bias due to deconditioning in COPD patients.

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

Probably not a substantial claim: may not pass S3 (load-bearing).

Timmons and colleagues identified 11 SNPs associated with the increase in maximal oxygen uptake (VO2max) after exercise training in the general population.

“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].”

• cites [150] Timmons, 2010, Using Molecular Classification to Predict Gains in Maximal Aerobic Capacity Following Endurance Exercise Training in Humans, J. Appl. Physiol. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Epigenetic modifications are believed to control muscle fiber type and can be influenced by external factors such as nutrition.

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

• cites [153] Baar, 2010, Epigenetic Control of Skeletal Muscle Fibre Type, Acta Physiol. sourceNot checked — no full text of the source

May combine two claims.

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

“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].”