Project Summary/Abstract
Skeletal muscle mass loss during cancer cachexia is one of the most important predictors of poor prognosis
and mortality among cancer patients. However, the role played by skeletal muscle mass in the survival of
cancer patients has been understood as a mere symptom of poor overall body health. Contrary to this notion,
recent studies have demonstrated that skeletal muscle has an independent and active role in improving
survival among cancer patients. Proof-of-principle investigations have shown that promoting skeletal muscle
mass, for instance by blocking myostatin signaling, can increase lifespan in tumor-bearing mice independently
of any effect of the drug on tumor volume. Therefore, understanding the mechanism regulating muscle size
can lead to better therapeutic targets to improve health outcomes among advanced cancer patients.
Ribosome biogenesis, the de novo synthesis of ribosomes, is a key process determining protein synthesis in
skeletal muscle. While there has been great attention recently to the roles of muscle ribosome biogenesis in
regulating muscle hypertrophy, the roles of muscle ribosome biogenesis to maintain muscle mass and during
muscle atrophy are largely unknown. We have generated a mouse strain in which we can lower ribosome
biogenesis specifically and conditionally in skeletal muscle. We crossed the Upstream Binding Factor (UBF, a
key transcriptional factor important for ribosomal DNA transcriptional) floxed mouse to the muscle specific
human a-skeletal actin (HSA) promoter linked to a CRE recombinase (HSA-MCM). Using this mouse model to
reduce UBF levels in adult muscles only (which we termed UBF mKO), we showed impairing muscle ribosome
biogenesis causes muscle atrophy particularly in type IIb and IIx myofibers, while Type I and IIa fibers are not
affected. Unexpectedly, long-term experiments using the UBF mKO mice demonstrated that impaired muscle
ribosome biogenesis have severe consequences to muscle and whole-body metabolism that phenocopied
cancer cachexia, including high respiratory exchange ratio (RER) and depletion of adipose tissue. With our
reversed engineered mouse model, we were able to recreate cancer cachexia from within muscle, challenging
the assumption that skeletal muscle wasting in cancer cachexia is a mere effect of systemic disease. Rather,
our preliminary data strongly suggest that cachexia in the whole body can be initiated in skeletal muscle. This
proposal seeks to investigate the mechanism of muscle wasting via skeletal muscle and to identify the
mechanism leading to overall cachectic phenotype. If our hypothesis is correct, this will be the first evidence
that muscle wasting in cachexia can be recreated from within the muscle tissue and that muscle ribosome
biogenesis could be a target to mitigate or even abolish cancer cachexia altogether.
