| dc.description.abstract | Cancer cachexia is a complex syndrome associated with multiple factors results in ongoing muscle
and fat loss that is not completely reversible by nutritional supplementation. Skeletal muscle wasting is
the most severe side effect in cachexia, and the underlying molecular mechanisms are largely unknown.
To understand the mechanisms involved in cancer cachexia, we used cancer cachectic xenograft mice,
induced cancer cachexia, and collected their tissues for RNA-seq analysis. In the RNA-seq data, we
observed severe down-regulation of Mef2c, and found through tissue sections that central cell nuclei
were significantly increased in cancer cachexia, confirming the impact of cancer cachexia on muscle
regeneration, and Mef2c is involved in the regulation of Mrf4. Mrf4 negatively regulates skeletal muscle
growth by inhibiting Mef2 activity. To investigate the relationship between Mef2c and Mrf4 in cancer
cachexia, we induced overexpression of Mef2c and Mrf4 in C2C12 cells. Surprisingly, we observed that
Mef2c-overexpressing cells were poorly differentiated with respect to myogenesis and atrophy. We
believe that Mef2c isoform 1 has low myogenic activity in myogenesis and atrophy, and its myogenic
capacity is not restored by overexpression of Mef2c. At the same time, we observed that inducing Mrf4
overexpression successfully resulted in higher myogenicity, indicating that Mrf4 levels have a critical
regulatory role in the myogenic process. However, even in myogenesis, Mrf4 overexpression failed to
rescue the myogenesis ability of C2C12-Mrf4 cells after being treated with cancer cachexia culture
medium. Interestingly, the RNA and protein of Mrf4 are not inhibited by cancer cachexia, but inhibit
the function of Mrf4 in muscle regeneration. In order to investigate this situation, I used triple alignment
to select the binding site genes of Mrf4 and discovered the downstream The gene Kcnn3 is regulated by
cancer cachexia and Mrf4, confirming that cancer cachexia may affect the expression ability of Mrf4 by
affecting downstream gene binding sites.In conclusion, this paper confirms that the abnormal muscle
status of cancer cachexia cannot be rescued by excessive expression of Mef2c and Mrf4, but in the future,
we can further find ways to rescue it by investigating the new mechanism of Mrf4. | en_US |