Activation of the SDF1/CXCR4 pathway retards muscle atrophy during cancer cachexia

Abstract

Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 (SDF1), adenylate cyclase 7 (ADCY7), and p21 protein-activated kinase 1 (PAK1). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, β, γ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1β had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.

Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia

“…The study also showed that the levels of SDF1 isoforms were reduced in muscle of cachectic mice. 60 Although SDF1 did not meet the predefined cut-off for DASG, a similar trend was also observed in our study (down-regulated in cachectic cases when compared with WS cancer patients, data not shown). It would be interesting to further investigate if this pathway can be targeted for potential interventions for human CC.…”

“…Our IPA analysis also predicted CXCR4 signalling pathways to be associated with CC. Martinelli et al ., recently showed that down‐regulation of genes involved in this pathway led to muscle wasting in Yoshida hepatoma‐bearing rodents and subsequent activation‐reduced muscle wasting. The study also showed that the levels of SDF1 isoforms were reduced in muscle of cachectic mice .…”

“…Martinelli et al ., recently showed that down‐regulation of genes involved in this pathway led to muscle wasting in Yoshida hepatoma‐bearing rodents and subsequent activation‐reduced muscle wasting. The study also showed that the levels of SDF1 isoforms were reduced in muscle of cachectic mice . Although SDF1 did not meet the predefined cut‐off for DASG, a similar trend was also observed in our study (down‐regulated in cachectic cases when compared with WS cancer patients, data not shown).…”

Group I Paks support muscle regeneration and counteract cancer‐associated muscle atrophy

“…Moreover, in skeletal muscle, Pak1 has been associated with the regulation of glucose uptake through insulin‐induced Glut4 translocation and in contraction modulation by phosphorylating Myosin Light Chain Kinase . In addition, we have recently shown that Pak1 is down‐regulated in atrophying gastrocnemius of Yoshida hepatoma‐bearing rats and others have reported it to be up‐regulated in soleus muscles following Axokine administration . All this evidence points to a central role of Pak1 in processes related to muscle physiology.…”

“…Cachexia appears in nearly 50% of patients with advanced stage of cancer and leads to progressive functional impairment, decreased quality of life with respiratory complications, and death can occur following the loss of ~75% of skeletal muscle mass . We have recently found that three genes encoding for proteins of the C‐X‐C motif chemokine receptor 4 pathway are down‐regulated in the atrophying gastrocnemius of Yoshida hepatoma‐bearing rats: stromal cell‐derived factor 1, adenylate cyclase 7, and p21 protein‐activated kinase 1 (Pak1) …”