Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model

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.

Cachexia and sarcopenia: mechanisms and potential targets for intervention

“…Different research groups have shown that, in spite of the fact that the UCP2 gene is overexpressed in skeletal muscle from cachectic rats [14,15] and that muscle oxidative capacity -complex IV activity -is decreased, no alteration in either ATP synthesis or uncoupling are observed. These results are in contrast to the observation from our own research group where both ATP synthesis is decreased [16] and uncoupling is present [17] in mitochondria from tumour-bearing mice ( Figure 1). Other groups have found similar results demonstrating decreased ATP synthesis in skeletal muscle during cancer cachexia [18].…”

Cachexia: a problem of energetic inefficiency

“…In fact, Masaki et al have demonstrated that TNF regulates the in vivo expression of the UCP family differentially and tissue dependently [48]. A very recent data from our laboratory clearly indicate that uncoupling of oxidative phosphorylation is present in skeletal muscle of tumour-bearing animals [49]. Therefore, this phenomenon contributes, during the cachectic syndrome, to the generation of energetic inefficiency and, ultimately, to body weight loss.…”

Aerobic exercise training as therapy for cardiac and cancer cachexia

“…However, the current lack of success for a single therapy indicates that cancer cachexia intervention may include different approaches, including non-pharmacological strategies, such as AET ( [32]; [5,90]). During cachexia progression, skeletal muscle endurance capacity is severely reduced [21,35,92,95]. The oxidative metabolism dysfunction, insulin resistance and increased glycolysis have been attributed to skeletal muscle mitochondrial dysfunction and the hypoxic environment of the tumor, mainly due to hypoxia-inducible transcription factors [33].…”