Interleukin 6 as a key regulator of muscle mass during cachexia

Abstract

Interleukin 6 (IL-6) has received significant attention for its regulatory role in muscle wasting during cachexia. This review examines the role of circulating IL-6 for decreasing muscle mass during cancer and emphasizes some of the indirect actions of IL-6 that may cause muscle wasting.

Figures

Figure 1. The dependence of IL-6 on muscle wasting and tumor formation

Wild-type (WT), ApcMin/+ (MIN), ApcMin/+ / IL-6−/− mice (MIN IL-6 KO) were analyzed at 6 months of age for gastrocnemius muscle mass, total intestinal polyp number, and circulating IL-6. IL-6 or an empty vector was over-expressed in the circulation in ApcMin/+ / IL-6−/− mice (MIN IL-6 KO + VECTOR and MIN IL-6 KO + IL-6) and WT mice (WT + VECTOR and WT + IL-6). Treatment was done for 10 weeks and muscle mass, polyp counts, and circulating IL-6 were also analyzed at 6 months of age. ND=not detected. Figure 1 was created originally by the author and has not been previously published.

Figure 2. The relationship between muscle wasting, circulating IL-6, and physical activity levels in cachectic ApcMin/+ mice

ApcMin/+ mice were given access to voluntary activity wheels starting at 5 weeks of age until 26 weeks of age. At the study's end, mice were stratified by their degree of wasting, which was dependent upon body mass, gastrocnemius muscle mass, and epididymal fat pad mass. A. Gastrocnemius muscle mass, total polyps, and plasma IL-6 in mice with mild or severe cachexia. B. Body mass loss occurs after changes in physical activity. Physical activity was measured as maximum daily running velocity and daily distance run. *Signifies different from mice with mild cachexia. Figure 2 was created originally by the author and has not been previously published.

Figure 3. Exercise training reduces the polyp burden and circulating IL-6 in young ApcMin/+ mice

Male ApcMin/+ mice were sedentary (Control), exercise trained (Treadmill), or given access to voluntary activity wheels (Activity Wheel) from 4 to 13 weeks of age. At the study's end, gastrocnemius muscle mass, total polyps, and circulating IL-6 levels were analyzed. Mice in activity wheels ran approximately 4 times more than mice on the treadmill. Daily spontaneous activity was not determined (ND) for Control mice. *Signifies different from Control. #Signifies different from Treadmill. Figure 3 was created originally by the author and has not been previously published.

Figure 4. Theoretical model of IL-6 regulation of muscle wasting in the ApcMin/+mouse

The increase in intestinal and colon tumor number and size increases systemic inflammation and circulating IL-6, which can act as a positive feedback signal to increase tumor growth and subsequent inflammation. IL-6 can directly influence muscle protein turnover through suppression of protein synthesis and activation of protein degradation. Indirect effects of IL-6 through the induction of adipose tissue lypolysis cause metabolic stress in the cachectic muscle. Figure 4 was created originally by the author and has not been previously published.