IL-6 regulates mitochondrial remodeling in skeletal muscle during cancer cachexia in the ApcMin/+ mouse


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.

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Posted on behalf of Jennifer R. Levy.