Too rigid to strike: Excess desmin at Z-discs underlies a restrictive cardiomyopathy in GAN mice

Restrictive cardiomyopathy (RCM) is characterized by myocardial stiffness and impaired diastolic filling. While human giant axonal neuropathy (GAN) is linked to RCM with desmin accumulation, the underlying mechanisms remain unclear. We combined 3D tissue staining, electron microscopy, and echocardiography to investigate RCM phenotypes in GAN mice. Phenotypic profiling revealed atrial enlargement and impaired diastolic relaxation. Ultrastructural analysis demonstrated shortened I-bands and widened, hyper-dense Z-discs, correlating with elevated desmin density at Z-discs. To elucidate the biophysical principles driving this pathology, we developed an AI-guided multiscale computational model simulating the progression from molecular overcrowding to macro-level organ dysfunction. The modeling indicates that excess desmin crowding promotes aberrant inter-filament contacts, reduces linker-12 compliance, limits Z-disc elastic recoil, and physically restricts diastolic I-band re-extension. Collectively, our multidisciplinary findings establish an experiment-constrained mechanical framework linking desmin proteostasis failure to restrictive sarcomere dysfunction.