Expression of the lipid-binding-defective DNM2 K562E mutant fully rescued survival, motor function, and muscle force in the Mtm1-/y mouse model of centronuclear myopathy.
Does disrupting DNM2 lipid binding via the K562E mutation improve muscle pathology and survival in Mtm1-/y mouse models of centronuclear myopathy?
DNM2 lipid binding, rather than protein abundance or GTPase activity, drives centronuclear myopathy pathology and represents a rational therapeutic target.
Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in MTM1 or DNM2, encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in MTM1-CNM patients and Mtm1-/y mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and Mtm1-/y mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In Mtm1-/y mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated Mtm1-/y Dnm2K562E/+ mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in MTM1-CNM.
Gómez-Oca et al. (Thu,) conducted a other in Centronuclear myopathy. AAV-delivered DNM2 K562E mutant vs. AAV-empty or WT DNM2 was evaluated. Expression of the lipid-binding-defective DNM2 K562E mutant fully rescued survival, motor function, and muscle force in the Mtm1-/y mouse model of centronuclear myopathy.