The Apc(Min/+) mouse has a mutation in the Apc tumor suppressor gene and develops intestinal polyps, beginning at 4 wk of age. This mouse develops cachexia by 6 mo, characterized by significant loss of muscle and fat tissue. The purpose of the present study was to determine the role of circulating interleukin-6 (IL-6) and the polyp burden for the development of cachexia in Apc(Min/+) mice. At 26 wk of age, mice exhibiting severe cachectic symptoms had a 61% decrease in gastrocnemius muscle weight, complete loss of epididymal fat, a 10-fold increase in circulating IL-6 levels, and an 89% increase in intestinal polyps compared with mildly cachectic animals. Apc(Min/+)/IL-6(-/-) mice did not lose gastrocnemius muscle mass or epididymal fat pad mass while overall polyp number decreased by 32% compared with Apc(Min/+) mice. Plasmid-based IL-6 overexpression in Apc(Min/+)/IL-6(-/-) mice led to a decrease in gastrocnemius muscle mass and epididymal fat pad mass and increased intestinal polyp burden. IL-6 overexpression did not induce cachexia in non-tumor-bearing mice. These data demonstrate that IL-6 is necessary for the onset of adipose and skeletal muscle wasting in the Apc(Min/+) mouse and that circulating IL-6 can regulate Apc(Min/+) mouse tumor burden.

Many diseases are associated with catabolic conditions that induce skeletal muscle wasting. These various catabolic states may have similar and distinct mechanisms for inducing muscle protein loss. Mechanisms related to muscle wasting may also be related to muscle metabolism since glycolytic muscle fibers have greater wasting susceptibility with several diseases. The purpose of this study was to determine the relationship between muscle oxidative capacity and muscle mass loss in red and white hindlimb muscles during cancer cachexia development in the Apc Min/+ mouse. Gastrocnemius and soleus muscles were excised from Apc Min/+ mice at 20 wk of age. The gastrocnemius muscle was partitioned into red and white portions. Body mass (−20%), gastrocnemius muscle mass (−41%), soleus muscle mass (−34%), and epididymal fat pad (−100%) were significantly reduced in severely cachectic mice ( n = 8) compared with mildly cachectic mice ( n = 6). Circulating IL-6 was fivefold higher in severely cachectic mice. Cachexia significantly reduced the mitochondrial DNA-to-nuclear DNA ratio in both red and white portions of the gastrocnemius. Cytochrome c and cytochrome- c oxidase complex subunit IV (Cox IV) protein were reduced in all three muscles with severe cachexia. Changes in muscle oxidative capacity were not associated with altered myosin heavy chain expression. PGC-1α expression was suppressed by cachexia in the red and white gastrocnemius and soleus muscles. Cachexia reduced Mfn1 and Mfn2 mRNA expression and markers of oxidative stress, while Fis1 mRNA was increased by cachexia in all muscle types. Muscle oxidative capacity, mitochondria dynamics, and markers of oxidative stress are reduced in both oxidative and glycolytic muscle with severe wasting that is associated with increased circulating IL-6 levels.

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

Overall, estrogen-based treatments were found to beneficially affect strength.

Interleukin-6 (IL-6) is necessary for cachexia in Apc Min/+ mice, but the mechanisms inducing this myofiber wasting have not been established. The purpose of this study was to examine gastrocnemius muscle wasting in the Apc Min/+ mouse and to determine IL-6 regulated mechanisms contributing to muscle loss. Gastrocnemius type IIB mean fiber cross-sectional area (CSA) from Apc Min/+ mice decreased 32% between 13-and 22-wks of age. Apc Min/+ mice lacking IL-6 did not have type IIB fiber atrophy, while over-expression of circulating IL-6 exacerbated the loss of type IIB fiber CSA in Apc Min/+ mice. Muscle Atrogin-I mRNA expression was induced at least 9-fold at 18-and 22-wks of age compared to 13-wk-old mice. Atrogin-I gene expression was also induced by over-expression of circulating IL-6. These data suggest that high circulating IL-6 levels induce type IIB fiber CSA loss in Apc Min/+ mice, and circulating IL-6 is sufficient to regulate Atrogin-I gene expression in cachectic mice.