Increasing BIN1 or decreasing DNM2 worsens pathology in a mouse model of dysferlinopathy.

Dysferlinopathies are rare muscular dystrophies caused by loss-of-function variants in DYSF, which encodes dysferlin, leading to progressive muscle weakness. Although dysferlin is known for its role in membrane repair, emerging evidence suggests additional functions in membrane remodeling and T-tubule organization. Therapeutic strategies targeting the BIN1-DNM2 axis have successfully rescued T-tubule and force defects in centronuclear myopathies, raising the possibility of broader applicability. Here, we evaluated whether BIN1 overexpression or DNM2 downregulation could improve disease features in dysferlin-deficient mice through genetic crosses. Unexpectedly, both modulations worsened the Dysf-/- phenotype. BIN1 overexpression increased necrosis, fibrosis and circulating MYOM3 levels. DNM2 downregulation produced an even more severe phenotype, including additional reduced force and fiber calcification. Importantly, DNM2 protein levels were intrinsically elevated in Dysf-/- mice and biopsies from patients with dysferlinopathy. Because both strategies reduced DNM2 levels and worsened the phenotype, the elevated DNM2 levels likely represent a compensatory rather than pathogenic mechanism. Our findings demonstrate that therapeutic modulation of the BIN1-DNM2 axis has disease-specific consequences. In dysferlinopathy, DNM2 upregulation may represent a compensatory mechanism required for membrane stability, underscoring the need for context-dependent therapeutic strategies.