Mulder, T. | bioRxiv Science

bioRxiv2026

Evidence of complete myofibril remodeling after severe damage in adult Drosophila.

Muscle function depends on the ability of myofibrils to withstand and repair mechanical damage, yet how adult muscles remodel damaged myofibrils remains poorly understood. Here, we establish a Drosophila model that allows the induction and longitudinal visualization of extensive myofibril damage and recovery in intact adult femur muscles. Sustained muscle depolarization caused extensive disruption of myofibrillar organization, with severe damage characterized by near-complete loss of Z-disc structures. Remarkably, myofibril architecture and muscle function were largely restored within days, revealing a substantial capacity for myofibril reconstruction in adult femur muscles. We identified two distinct states of myofibril damage, mild and severe, with mild damage appearing before severe damage during aging, suggesting a progressive process of myofibril deterioration and repair failure. We further show that filamins mechanosignaling is required for efficient myofibril remodeling. Following damage, wild-type filamin redistributes from the Z-disc and accumulates outside the myofibrils, whereas constitutively open filamin remains Z-disc-associated and constitutively closed filamin redistributes but results in increased damage and impaired recovery. These findings suggest that effective repair requires dynamic transitions between filamin conformational states and that filamin redistribution is an active component of the damage response rather than simply a consequence of muscle injury. During aging, filamin progressively redistributes from the Z-disc and muscle damage accumulates, with severe damage increasing after the appearance of mild damage. Together, our findings reveal a previously unappreciated capacity of adult muscle to reassemble damaged myofibrils and identify filamin mechanosignaling as a key component of this repair process, providing a framework for understanding how defective mechanosensing may contribute to age-related muscle decline and muscle disease.

cell biology↗

bioRxiv2023

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

Filamins 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.

cell biology↗