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Abstract
Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel ‘fragmented mass isotopomer’ approach was used in our dynamic analysis of 13C mass isotopomer data. Our 31P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochondrial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t-test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging.
Highlights
Half of all cancer patients, those with cancers of the gastrointestinal tract and lung [1,2,3], present with cachexia, in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass [4], resulting in a body weight reduction of ≥30% [5]
We discovered that the unidirectional synthesis rate of the Pi → γ-adenosine triphosphate (ATP) reaction in the mice in the TB group was 49% lower compared to that observed in the mice in the C group (p=0.008)
The principle finding of this study was that tricarboxylic acid (TCA) cycle flux determined by mass spectrometry was significantly reduced in mice in the TB group, compared to those in the C group
Summary
Half of all cancer patients, those with cancers of the gastrointestinal tract and lung [1,2,3], present with cachexia, in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass [4], resulting in a body weight reduction of ≥30% [5]. Our hypothesis is based on our previous studies on experimental models of muscle wasting [62,63,64,65,66,67,68,69,70,71]. Colon 26 adenocarcinoma is an appropriate model for examining cachexia [73,74,75] and murine adenocarcinoma 16 (MAC16 adenocarcinoma) is a well-established model for studies on human gastrointestinal and pancreatic cancers [76]. Muscle data obtained from mice bearing MAC16 tumors [77] are in agreement with human muscle biopsy data [78] and are suggestive of mitochondrial uncoupling
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