Preserved muscle oxidative metabolic phenotype in newly diagnosed non‐small cell lung cancer cachexia

Abstract

BackgroundCachexia augments cancer-related mortality and has devastating effects on quality of life. Pre-clinical studies indicate that systemic inflammation-induced loss of muscle oxidative phenotype (OXPHEN) stimulates cancer-induced muscle wasting. The aim of the current proof of concept study is to validate the presence of muscle OXPHEN loss in newly diagnosed patients with lung cancer, especially in those with cachexia.MethodsQuadriceps muscle biopsies of comprehensively phenotyped pre-cachectic (n = 10) and cachectic (n = 16) patients with non-small cell lung cancer prior to treatment were compared with healthy age-matched controls (n = 22). OXPHEN was determined by assessing muscle fibre type distribution (immunohistochemistry), enzyme activity (spectrophotometry), and protein expression levels of mitochondrial complexes (western blot) as well as transcript levels of (regulatory) oxidative genes (quantitative real-time PCR). Additionally, muscle fibre cross-sectional area (immunohistochemistry) and systemic inflammation (multiplex analysis) were assessed.ResultsMuscle fibre cross-sectional area was smaller, and plasma levels of interleukin 6 were significantly higher in cachectic patients compared with non-cachectic patients and healthy controls. No differences in muscle fibre type distribution or oxidative and glycolytic enzyme activities were observed between the groups. Mitochondrial protein expression and gene expression levels of their regulators were also not different.ConclusionMuscle OXPHEN is preserved in newly diagnosed non-small cell lung cancer and therefore not a primary trigger of cachexia in these patients.

The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting

“…Insulin sensitivity as well as lipid metabolism are impaired in cancer patients with recent weight loss [7] . However, in lung cancer patients exhibiting significant weight loss muscle oxidative capacity has been reported to be preserved [48] . Further study is needed to determine the relationship between muscle oxidative capacity declines and the specific type of cancer; lung cancer can promote rapid weight loss, which could differentially affect oxidative capacity when compared to less aggressive body weight loss.…”

“…Interestingly, in cachectic cancer patients there is evidence for the induction of muscle autophagy-lysosomal processes, while activation of the ubiquitin proteasome system in human cancer patients is more equivocal [122,123,128–130] . Also, the link between oxidative metabolism and autophagy is less clear in humans; a decrease in muscle oxidative metabolism has not been reported in some cachectic human cancer patients [48] . As it relates to physical activity, oxidative muscle fibers display higher levels of autophagy flux [131] , and exercise can stimulate autophagy [131–133] .…”

“…IL-6 is a pleiotropic cytokine that has been implicated in the regulation of skeletal muscle metabolism and cachexia in both animal models and cancer patients [48,145,161–163] . IL-6 binding to its receptor complex can activate several intracellular signaling pathways including JAK/STAT signaling.…”

Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?

“…50 While a significant reduction in the cross-sectional area of muscle fibres was observed in gastrointestinal cancer patients with cachexia and muscle loss, 46,51 Op den Kamp et al found no such change in cachectic patients with advanced non-small-cell lung cancer compared with pre-cachectic patients. 52 Finally, no significant alteration in fibre typing associated with cancer cachexia has been reported in clinical studies, either of gastrointestinal 51,53 or lung 54 cancer.…”

“…71 Op den Kamp et al have also reported an absence of modification of the protein expression of the same markers of mitochondrial biogenesis (PGC1α and TFAM), as well as complexes of the respiratory chain in cachectic patients suffering from pulmonary cancer. 54 On the other hand, Collins et al have observed increased UCP-3 (but not UCP-2) mRNA expression levels in patients with gastrointestinal adenocarcinoma experiencing weight loss. 72 This finding suggests that increased proton leak may contribute to skeletal muscle catabolism through enhancement of energy expenditure.…”