Induction of interleukin-6 by adjuvant breast cancer treatment in mice promotes loss of lean body mass via down-regulation of insulin-like growth factor I: the role of AMP-activated protein kinase (AMPK)

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Breast cancer (BC) patients undergoing adjuvant chemotherapy, particularly with Adriamycin containing regimes, often experience loss of lean body mass, which can affect quality of life and physical functioning during treatment and sometimes years after treatment has ended. The purpose of this study was to determine whether the induction of interleukin-6 (IL-6) by Cytoxan-Adriamycin-5-Fluourouracil (CAF), a common adjuvant BC chemotherapy regime, mediates the effects of treatment on lean body mass. CAF treatment in 8-10 week old female C57BL/6 mice increased plasma IL-6 levels, which peaked at 3-6 hours post-treatment. To determine the source of plasma IL-6 following CAF administration, we measured IL-6 mRNA levels in spleen, duodenum, skeletal muscle, and liver and found that CAF specifically lead to the accumulation of IL-6 mRNA in skeletal muscle that paralleled the increase in plasma IL-6 levels. AMP-activated protein kinase (AMPK) plays a central role in the regulation of energy homeostasis in skeletal muscle and we have found that it is an important regulator of IL-6. We found that Adriamycin activated AMPK in murine C(2)C(12) myotubes in a dose dependent manner leading to production of IL-6. Experiments are currently underway to determine the role of AMPK in CAF mediated induction of IL-6 in vivo. The effects of CAF administration on daily food intake, physical activity, and body weight in female C57BL/6 mice were determined during the course of 4 treatments administered at 3-week intervals. Mice administered 4 cycles of CAF displayed a reduction in food intake, body weight, and physical activity during treatment relative to sham-injected mice. Weight loss in drug-treated mice was related to a significant reduction in lean body mass, but not fat mass as determined by dual energy X-ray absorptiometry (DEXA). Increased IL-6 levels in skeletal muscle has been implicated in muscle wasting via possible down-regulation of insulin-like growth factor I (IGF-1) production. We found that IL-6 induction was followed by a significant decline in IGF-1 levels in both plasma and skeletal muscle. IL-6 deficient mice were protected from the loss of lean body mass during CAF treatment independent of food intake or physical activity. Taken together our findings suggest that adjuvant BC chemotherapy can 1) induce IL-6 production by skeletal muscle both in vitro and in vivo possibly via activation of AMPK and 2) promote loss of lean body mass via IL-6 mediated down-regulation IGF-1. This work has the potential to lead to new targeted strategies aimed at improving quality of life and physical functioning in women undergoing adjuvant BC chemotherapy.