Researchers from the Physiopathology of the Cytoskeleton Group [collaboration] have determined CLIMP-63 as the missing link between triadine and microtubules, two molecular actors in muscle contraction. This discovery paves the way toward a better understanding of certain severe cardiac pathologies and certain myopathies.
Muscle contraction is triggered by a massive release of calcium inside the muscle cells at the level of membrane structures called triads. Although the molecular mechanisms involved in the formation and maintenance of triads are still poorly understood, at least two actors have been identified: triadin, a protein with shaping properties on the triads; and microtubules, the "nervous system" of the cell, whose organization in the form of a highly-structured fibrillar grid in muscle cells suggests that they may be involved in the maintenance and organization of triads. Given the indirect link between triadine and microtubules, finding the missing link between these two molecular actors in muscle contraction was a real challenge.
Researchers from the Institute of Neuroscience of Grenoble (Cell Myology and Pathologies team) and from our institute (Physiopathology of the Cytoskeleton Group and Large Scale Biology laboratory) have recently identified and characterized the CLIMP-63 protein as this missing link, providing the first demonstration of its role in skeletal muscle. Their findings show that CLIMP-63 is not only localized in several membrane compartments, including the triads, but is also able to bind directly to the microtubules. The direct involvement of this protein was confirmed when the researchers observed a disorganization of the microtubule network after introducing a mutant form of CLIMP-63 into a mouse muscle.
By demonstrating the essential role of the triadine-CLIMP-microtubules trio in the physiology of muscle cells, this study opens the way toward a better understanding of certain human pathologies. Indeed, human genetic variations of triadine are known to be responsible for severe heart pathologies and myopathies. Given the strong link between triadine and CLIMP-63, it is likely that genetic variants of the human protein CLIMP-63 also cause muscle or cardiac pathologies. These variants of CLIMP-63 have yet to be identified.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.