Hunger causes cellular remodeling.
When nutrients are not taken from food, the cellular metabolism has to readjust and it does so thanks to a newly discovered mechanism.
Researchers have gained new insights into a key mechanism in human cells by studying a rare genetic muscle disorder, X -linked centronuclear myopathy (XLCNM). This disease, which usually affects boys, is caused by a defective gene on the X chromosome, which causes skeletal muscle development disorder. The muscle weakness is so severe that, in many cases, affected children require ventilator support and are wheelchair-bound. Affected individuals do not survive beyond 10-12 years of age; in severe cases, they die shortly after birth.
The genetic defect present in this disease affects the MTM1 lipid phosphatase . This enzyme controls the turnover of a signaling lipid on endosomes, cell structures whose job is to participate in endocytosis, i.e. the cellular mechanism that allows transit through the cell membrane. In particular, endosomes are involved in the sorting of nutrient receptors. It was while studying the structure of mutated human muscle cells in patients that researchers discovered changes in the endoplasmic reticulum (ER), a membrane network that runs through the entire cell. “Muscles are very sensitive to hunger; their energy reserves soon run out. We then began to suspect that the defect in the XLCNM patients’ cells could be linked to an incorrect response to starvation ,” Volker Haucke reported. When cells are starved, an amino acid deficiency occurs.
However, fat cannot be transported or burned efficiently in cells deficient in the MTM1 gene. The endosome controlled by the MTM1 gene plays a key role in this process. In healthy cells, hunger reduces the contact points between endosomes and the endoplasmic reticulum. The endoplasmic reticulum is a membrane system typical of eukaryotic cells. It represents the largest and most adaptable compartment of eukaryotic cells. It consists of a three-dimensional system of membranes joined together. These membrane compartments take various forms, including cisternae (flattened sacs), tubules and vesicles and are extremely mobile and dynamic, changing their shape and extent during the various phases of the cell cycle, allowing the latter to remodel itself accordingly.
In cells from XLCNM patients, voral remodeling does not occur, there is no reduction of contact sites. “We have discovered a completely new mechanism for understanding how the different compartments of the cell communicate with each other so that the cellular metabolism adapts in response to the food supply,” Volker Haucke summarized. In light of this, the current study proves that starvation is totally harmful to the muscle cells of XLCNM patients. They need a constant supply of food to prevent muscle protein from being broken down into amino acids. In a second study, the researchers were able to demonstrate that defects due to loss of lipid phosphatase MTM1 can essentially be repaired by inactivating the “opposite” enzyme, lipid kinase PI3KC2B. Only time will tell if this will work in XLCNM patients. The team led by Volker Haucke is currently working on finding a suitable inhibitor to suppress PI3KC2B activity. They have already demonstrated in cell culture that this is possible.
