The Bromodomain inhibitor JQ1 prevents skeletal muscle loss during cancer cachexia

Skeletal muscle wasting is a hallmark of cancer cachexia. This metabolic syndrome is responsible for about 25% of cancer deaths. In particular, muscle loss in cachectic patients often leads to increased morbidity and mortality, decreased beneficial effects from chemotherapeutic treatment, and poorer quality of life. Therefore, the development of therapeutic avenues addressed at preventing muscle wasting during cancer cachexia is attracting increasing clinical interest. To date, no effective therapies for cachectic muscle are available. Recently, our research group reported that the small bromodomain inhibitor JQ1 enhances muscle fiber size and protects from dexamethasone-induced muscle atrophy in C2C12 myotubes, by blocking skeletal muscle pro-atrophic pathways, triggered by myostatin. In the present work we evaluated the effect of JQ1 treatment in skeletal muscle wasting during cancer cachexia. To this aim, C26 (adenocarcinoma cell line) bearing mice were chronically treated with JQ1 or vehicle. After 12 days, body weight, skeletal muscle weight and the anabolic/catabolic pathways involved in skeletal muscle homeostasis were analyzed. The results show that JQ1 treatment blocks muscle-specific ubiquitin ligases expression, and protects tumor-bearing mice from body weight loss and muscle wasting. Furthermore, JQ1 administration prevents adipose tissue loss and restores lipids levels in the blood. These results suggest that the epigenetic modulation mediated by bromodomain inhibitors may represent a promising therapeutic approach in the management of muscle wasting during cancer cachexia.