Organ regression, such as the regression seen in the post-prandial python heart after hypertrophy, could occur due to apoptosis or atrophy of the heart cells. Cardiac cells in the post- prandial python are not proliferating during heart growth, therefore it is unlikely that regression of the heart is due to loss of the cell that are already present. One mechanism that may play an important role in facilitating atrophy, or shrinking the cell size, after cardiac hypertrophy in mice is autophagy. Autophagy is a process mediating degradation and recycling of unnecessary or defective cytoplasmic components. Autophagy begins with the formation of an autophagosome. The autophagosome engulfs cytoplasm, which includes substances targeted for degradation. The autophagosome fuses with a lysosome and degrades the material it has collected to be recycled for nutrients. A baseline level of autophagy prevents build up of long-live proteins and organelles that could trigger apoptotic cell death. In mice, induction of autophagy is observed during the regression of pathological cardiac hypertrophy after removal from hemodynamic stress. Autophagy may also have an important role in mediating physiololgical heart regression in the python.*
Autophagy is regulated by numerous autophagy-related genes. Atrogin (Atg)-5 is part of a class of proteins that are involved in the core machinery of autophagy. These proteins are the key components for the initial formation of an autophagosome. Atg5 specifically participates in a ubiqutination-like pathway that recruits lipids that build the membrane of the autophagosome. In the pathway, Atg5 forms an irreversible complex with Atg12 and Atg16L1. This complex has E3 enzyme-like properties that facilitate the transfer of the ubiquitin-like protein, LC3, from Atg3 to the lipid substrate, phosphotidylethanolamine (PE) which then associates with the elongating phagophore of the autophagosome. Most of the existing LC3 is converted to the conjugate, LC3-PE, when autophagy is induced making it a key marker for autophagy. The Atg12-Atg5-Atg16L1 complex also associates with PE containing liposomes, suggesting that the complex could be involved in the localization of these liposomes during phagophore formation.*
In light of the important role of atrogins and autophagy in degradation of proteins in cells, the students hypothesized that this mechanism may be mediating cardiac regression after the Burmese python digests a meal. A set of genes was selected to represent most of the proteins in this pathway as well as genes involved in matrix remodeling and apoptosis. Student found that atrogin-related genes were upregulated beginning at 4 days after feeding, and expression of matrix metalloproteinases that mediate tissue remodeling increase during both cardiac hypertrophy and regression. In agreement with their hypothesis, genes involved in promoting apoptosis were not increased, while those that inhibit apoptosis were increased beginning at 3 days after feeding.
*adapted from a research paper written by Bailey Keller, student in the Fall 2013 Python Project