Cachexia severely limits therapeutic options in cancer patients, and is thought to cause about 20% of cancer deaths. Skeletal muscle mitochondria are emerging as critical mediators of muscle protein turnover during cancer cachexia. Using the severely cachectic ApcMin/+ mice, White and colleagues examined the role of IL-6 on the regulation of mitochondrial remodeling/dysfunction that precedes muscle proteolysis during cachexia. The authors had previously shown that inhibition of IL-6 signaling can attenuate the progression of cachexia. In the current study, they treated ApcMin/+ mice with an antibody against the IL-6 receptor and reduced the loss of mitochondrial biogenesis and content, compared to vehicle-treated mice. IL-6 inhibition also restored the altered mitochondrial fusion and reduced apoptosis observed in cachectic ApcMin/+ mice.
Excitingly, the authors found that exercise-training has a protective effect on IL-6 overexpression-induced muscle wasting in ApcMin/+ mice. Whereas IL-6 overexpression in sedentary animals decreased mitochondrial fusion protein expression and increased mitochondrial fission protein expression, IL-6 overexpressing mice that underwent 12 weeks of moderate treadmill training prevented these changes. Apoptosis, autophagy, and phosphorylation of FoxO, a potent regulator of muscle proteolysis, were also reduced in exercise-trained ApcMin/+ mice. Taken together, this paper shows that IL-6 is a central regulator of altered mitochondrial biogenesis and fusion in early cachexia, and that IL-6 induced mitochondrial remodeling and proteolysis can be rescued with exercise training.
Tocilizumab, a monoclonal antibody that inhibits the IL-6 receptor, is currently approved for use in patients with rheumatoid arthritis. It is interesting to speculate that this therapy has potential to manage cancer cachexia as well.
Posted on behalf of Jennifer R. Levy.