Skeletal muscle wasting — cachexia — is a common and debilitating syndrome that is estimated to contribute to a third of all cancer deaths. Anti-cachexia therapy is often ineffective, but a recent publication by Denis Guttridge and colleagues, which shows that tumour-induced changes in the dystrophin glycoprotein complex (DGC) are a key early event in cancer cachexia, has the potential to help improve these treatments.

Muscle-wasting disorders, such as Duchenne muscular dystrophy (DMD), are commonly associated with mutations in DGC components. The DGC provides a crucial mechanical link between the cytoskeleton and the extracellular matrix (ECM) in muscle cells, as well as being involved in signal transduction and membrane integrity.

Histological analysis of cachectic muscle tissue from a tumour-bearing mouse model of muscle wastage showed that membrane morphology was abnormal and membrane integrity was compromised in these tissues. Similar to the situation in DMD, levels of dystrophin were reduced in cachectic tissue, and levels of the related molecule, utrophin, were increased. The DGC-associated molecules α- and β-dystroglycan were also hyperglycosylated. Moreover, the DGC dissociated from the cytoskeleton–ECM axis in the cachectic tissues, which is probably due to these molecular changes. Similar changes were found in the DGC from a different cachectic tumour-bearing mouse model, which shows that changes in the DGC are characteristic of tumour-induced muscle wastage.

DGC deregulation is an underlying cause of cachexia in cancer...

Induced loss of DGC also exacerbates tumour-related muscle wasting — a severe atrophic effect was seen in tumour-bearing mice but not in otherwise normal mice. Furthermore, muscle-specific dystrophin expression in cachectic tumour-bearing mice rescued the cachexia phenotype, which provides further evidence for the crucial role of the DGC in this syndrome.

The muscle-specific E3 ubiquitin ligase, MuRF1, is involved in proteasome-mediated proteolysis in cachexia, and MuRF1 was found to be induced at around the same time that changes in the DGC are first detected. MuRF1 expression was also reduced in muscles in which the cachexia phenotype had been rescued by DGC expression, which together indicate that DGC dysfunction might regulate the ubiquitin–proteasome system.

Finally, DGC was found to be deregulated in cachetic cancer patients: 59% of 27 gastro-oesphageal adenocarcinoma patients had deregulated DGC, and 91% of patients with cachexia, who were selected using stringent parameters, had prominent DGC deregulation. Strikingly, 100% of the 10 non-surviving cases had DGC deregulation.

So, DGC deregulation is an underlying cause of cachexia in cancer as well as in muscular dystrophy, and restoration of this complex should be explored as a possible anti-cachexia treatment.