3 days popular7 days popular1 month popular3 months popular

Muscle weakness: scientists unravel defects in rare hereditary disease myotubular myopathy

Tiny deviations in the body’s cells can sometimes have severe consequences. Researchers from Berlin have discovered why cells from patients suffering from the rare muscular disease myotubular myopathy cannot function properly. Through the paper published in Nature, it has become clear how a dynamic cellular process essential to muscle development and function is regulated by means of minute changes of certain membrane lipids.

If a child is born with myotubular myopathy, the most severe form of centronuclear myopathies (also called XLCNM), it is barely able to breathe independently. The muscles are atrophied, the newborn lies limp in its mother’s arms and is too weak to feed. Babies with this rare muscular disease might not survive the first few months of their lives. The group of Volker Haucke from the Leibniz Institute for Molecular Pharmacology (FMP) and Freie Universität (FUB) in Berlin, in collaboration with the laboratories of Jocelyn Laporte from the Institut Génétique Biologie Moléculaire Cellulaire (IGBMC) in Strasbourg and Carsten Schultz at the European Molecular Biology Laboratory (EMBL) in Heidelberg, has been researching what goes wrong in this disease at the molecular level – and has now come across a general organizational principle in cells.

Up to now, it has been known that this hereditary disease involves a defect in the gene MTM1, as a result of which muscle fibers do not function normally. The gene codes for an enzyme that is specialized in cleaving phosphate groups from the heads of certain membrane lipids called phosphoinositide phosphates (PIPs) but how this leads to disease was unknown. PIPs are used by the cell to tag its compartments and to regulate the transport of substances. “The cell is a very dynamic system, which one can imagine as a metropolis in which the people move back and forth,” explains Volker Haucke. “Depending on the occasion, the people change their clothes – if you put on a dress coat, to some extent you assume a different identity than if you come along in jeans and sweatshirt, and you won’t be let in to the opera in pyjamas. In a similar manner, the compartments and transport vesicles within cells are constantly putting on different PIPs and thus change their identity.” Each PIP consists of a fat-soluble tail that is anchored in the membranes of the cell compartments, and a water-soluble head that protrudes from the membrane. The head can be loaded with phosphates at different sites, the phosphate groups are detached by enzymes and attached at other sites. This is a minimal change that takes place in a flash, yet it is unmistakably read by the cell. Thus, for example, if a phosphate group tags a certain position, it is clear that a transport container is supposed to be transported into the interior of the cell; if the phosphate tag is different, it migrates to the outer cell membrane, docks there, and unloads its freight to the outside.

Accumulation of integrin
Accumulation of integrin (red), an important component of muscles, in vesicles (green) from cells without MTM1 (right images including magnified view) or from control cells (left images including magnified view)
Image Credit: Katharina Ketel, Leibniz Institut für Molekulare Pharmakologie (FMP), Berlin