Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

Abstract

AbstractFilamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions either by providing elastic support or through signaling. The mechanistic details of filamin in this process are largely unknown. Here we use the indirect flight muscles of Drosophila to interrogate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region and detected two Z-disc phenotypes: dissociation of actin filamins and Z-disc rupture. We focused on the ruptured defect and tested a constitutively closed filamin mutant, which results in ruptured Z-discs, and a constitutively open mutant which gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We therefore propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, which induces myofibril repair.