ABSTRACT
Cancer patients commonly suffer from cachexia, a syndrome in which tumors induce metabolic changes in the host that lead to massive loss in skeletal muscle mass. Using a preclinical mouse model of cancer cachexia, we tested the hypothesis that tumor inoculation causes a reduction in ATP synthesis and genome-wide aberrant expression in skeletal muscle. Mice implanted with Lewis lung carcinomas were examined by in vivo 31P nuclear magnetic resonance (NMR). We examined ATP synthesis rate and the expression of genes that play key-regulatory roles in skeletal muscle metabolism. Our in vivo NMR results showed reduced ATP synthesis rate in tumor-bearing (TB) mice relative to control (C) mice, and were cross-validated with whole genome transcriptome data showing atypical expression levels of skeletal muscle regulatory genes such as peroxisomal proliferator activator receptor γ coactivator 1 ß (PGC-1ß), a major regulator of mitochondrial biogenesis and, mitochondrial uncoupling protein 3 (UCP3). Aberrant pattern of gene expression was also associated with genes involved in inflammation and immune response, protein and lipid catabolism, mitochondrial biogenesis and uncoupling, and inadequate oxidative stress defenses, and these effects led to cachexia. Our findings suggest that reduced ATP synthesis is linked to mitochondrial dysfunction, ultimately leading to skeletal muscle wasting and thus advance our understanding of skeletal muscle dysfunction suffered by cancer patients. This study represents a new line of research that can support the development of novel therapeutics in the molecular medicine of skeletal muscle wasting. Such therapeutics would have wide-spread applications not only for cancer patients, but also for many individuals suffering from other chronic or endstage diseases that exhibit muscle wasting, a condition for which only marginally effective treatments are currently available.
Subject(s)
Cachexia/physiopathology , Genomics/methods , Magnetic Resonance Spectroscopy/methods , Mitochondria/metabolism , Neoplasms/physiopathology , Adenosine Triphosphate/biosynthesis , Animals , Cachexia/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Mitochondria/pathology , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/metabolism , Muscular Atrophy/pathology , Neoplasm Transplantation , Neoplasms/metabolism , Random Allocation , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
C2C12 cells exposed to hyperthermia (41 degrees C) experienced an increase in both protein synthesis and degradation. The addition of IL15 under hyperthermic conditions resulted in an important increase in protein synthesis with no changes in protein degradation, except when cells overexpressed PPARdelta. The PPARdelta agonist GW501516 exerted similar effects on protein synthesis to IL15. Expression of a mutant dominant negative form of PPARdelta prevented the effect of the cytokine on protein synthesis, suggesting that this transcription factor is involved in the anabolic action of IL15. The present study also suggests that the effects of IL15 on lipid oxidation could be mediated by PPARdelta.
