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.