title: Consequences of Late-Stage Non-Small-Cell Lung Cancer Cachexia on Muscle Metabolic Processes.
abstract: The loss of muscle is common in patients with advanced non-small-cell lung cancer (NSCLC) and contributes to the high morbidity and mortality of this group. The exact mechanisms behind the muscle loss are unclear.
  
  
  
  To investigate this, 4 patients with stage IV NSCLC who met the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age-matched healthy volunteers. After an overnight fast, biopsy specimens were obtained from the vastus lateralis, and the key components associated with inflammation and the control of muscle protein, carbohydrate, and fat metabolism were assessed.
  
  
  
  Compared with the healthy volunteers, significant increases in mRNA levels for interleukin-6 and NF-κB signaling and lower intramyocellular lipid content in slow-twitch fibers were observed in NSCLC patients. Although a significant decrease in phosphorylation of the mechanistic target of rapamycin (mTOR) signaling protein 4E-BP1 (Ser65) was observed, along with a trend toward reduced p70 S6K (Thr389) phosphorylation (P = .06), no difference was found between groups for the mRNA levels of MAFbx (muscle atrophy F box) and MuRF1 (muscle ring finger protein 1), chymotrypsin-like activity of the proteasome, or protein levels of multiple proteasome subunits. Moreover, despite decreases in intramyocellular lipid content, no robust changes in mRNA levels for key proteins involved in insulin signaling, glycolysis, oxidative metabolism, or fat metabolism were observed.
  
  
  
  These findings suggest that examining the contribution of suppressed mTOR signaling in the loss of muscle mass in late-stage NSCLC patients is warranted and reinforces our need to understand the potential contribution of impaired fat metabolism and muscle protein synthesis in the etiology of cancer cachexia.
authors.affiliation: Division of Nutritional Sciences, School of Biosciences, The University of Nottingham, Loughborough, United Kingdom; MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Life Sciences, The University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom. Electronic address: andrew.murton@nottingham.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murton
authors.affiliation: Department of Palliative Medicine, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; King's College London, Cicely Saunders Institute, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Maddocks
authors.affiliation: MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Life Sciences, The University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom.
authors.forename: Francis B
authors.initials: FB
authors.lastname: Stephens
authors.affiliation: MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Life Sciences, The University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom.
authors.forename: Kanagaraj
authors.initials: K
authors.lastname: Marimuthu
authors.affiliation: Department of Palliative Medicine, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: England
authors.affiliation: Department of Palliative Medicine, The University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilcock
mesh_terms: D000230:Adenocarcinoma / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008055:Lipids / Q000032:analysis; D008175:Lung Neoplasms / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D008055:Lipids; D009124:Muscle Proteins; D046988:Proteasome Endopeptidase Complex
keywords: Lipid metabolism; Muscle protein synthesis; Proteolysis; Ubiquitin proteasome system; mTOR signaling