Relationship Between Mitogen-activated Protein Kinase Activity And Impaired Anabolic Signaling In Female ApcMin Mice

Previous studies have revealed sex-specific disparities during the development of cancer cachexia and the extent of muscle mass depletion. In male mice, the mitogen-activated protein kinases (MAPK), such as p38 and extracellular signal-regulated kinase 1/2 (ERK1/2), are known to play a role in muscle wasting in cancer cachexia. However, their role in female mice remains unclear. PURPOSE: The purpose of this study was to investigate whether alterations in the MAPK activity are associated with reduced anabolism in female cachectic muscle. METHODS: Female ApcMin/+ (Min, n = 4) mice and age-matched wild-type (WT, n = 4) mice were used. The body weights (BW) were recorded weekly, and all the mice were sacrificed at 22 weeks of age. The right gastrocnemius (GAS) muscles were removed, weighed, and snap-frozen at sacrifice. The tissues were homogenized for routine western blotting using 30 ~ 60 μg of the total protein. Student's t-test was used to compare the difference between WT and Min mice. The coefficient of determination (r^2) was used to examine a significant correlation. The level of significance was set at p < 0.05. RESULTS: Female Min mice had smaller BW (22.6 ± 0.3 g vs. 18.3 ± 1.7 g, for WT and Min mice, respectively, p < 0.05). Min mice lost 18.9% of BW compared to their peak BW. Likewise, GAS weight in Min mice was smaller than in WT mice (104.2 ± 4.9 mg vs. 80.8 ± 9.4 mg, respectively, p < 0.05). Western blot analysis showed that Min mice had a reduced phosphorylated state of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) than WT mice by 34% (1.0 ± 0.2 vs. 0.67 ± 0.2, respectively, p < 0.05). Conversely, p38 activity levels were elevated in Min mice by 63% (1.0 ± 0.2 vs. 1.6 ± 0.3, p < 0.05). ERK1/2 activity levels were comparable between the two mouse groups. There was a significant correlation between 4E-BP1 and p38 (r^2 = 0.6609, p < 0.05). No correlation was observed between 4E-BP1 and ERK1/2. CONCLUSIONS: These findings imply that p38, rather than ERK1/2, may play a role in promoting muscle wasting by suppressing an anabolic pathway in female cachectic mice.