Consequences of late-stage non-small cell lung cancer cachexia on muscle metabolic processes

• Published in: Clinical lung cancer Vol. 18; no. 1; pp. e1 - e11
• Main Authors: Murton, Andrew J, Maddocks, Matthew, Stephens, Francis B, Marimuthu, Kanagaraj, England, Ruth, Wilcock, Andrew
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017
• Subjects: Adenocarcinoma - complications; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Aged; Cachexia - etiology; Cachexia - metabolism; Cachexia - pathology; Carcinoma, Non-Small-Cell Lung - complications; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - complications; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Case-Control Studies; Female; Follow-Up Studies; Hematology, Oncology and Palliative Medicine; Humans; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Lipid metabolism; Lipids - analysis; Lung Neoplasms - complications; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; mTOR signaling; Muscle protein synthesis; Muscle Proteins - metabolism; Neoplasm Staging; Prognosis; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Pulmonary/Respiratory; Ubiquitin proteasome system; ubiquitin proteasome system; mTOR signalling; Muscle protein synthesis; proteolysis; cachexia; Lipid metabolism; mTOR signaling; Proteolysis; Ubiquitin proteasome system
• ISSN: 1525-7304; 1938-0690
• DOI: 10.1016/j.cllc.2016.06.003

Abstract Introduction 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 loss of muscle are unclear. Methods To investigate this, 4 patients with stage IV NSCLC meeting the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age-matched healthy volunteers. Following an overnight fast, biopsies were obtained from the vastus lateralis and key components associated with inflammation and the control of muscle protein, carbohydrate and fat metabolism assessed. Results Compared to healthy volunteers, significant increases in mRNA levels for interleukin-6 and NFκB signalling were observed in NSCLC patients along with lower intramyocellular lipid content in slow-twitch fibres. While a significant decrease in phosphorylation of mTOR signalling protein 4E-BP1 (Ser65 ) was observed along with a trend towards reduced p70 S6K (Thr389 ) phosphorylation (P=0.06), there was no difference between groups for mRNA levels of MAFbx and MuRF1, 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 signalling, glycolysis, oxidative metabolism or fat metabolism were observed. Conclusions These findings suggest that an examination of the contribution of suppressed mTOR signalling 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 aetiology of cancer cachexia.