Muscle-Specific DNM2 Overexpression Improves Charcot-Marie-Tooth Disease In Vivo and Reveals a Narrow Therapeutic Window in Skeletal Muscle.

ABSTRACT: Charcot-Marie-Tooth disease (CMT), caused by dominant loss-of-function mutations in DNM2, encoding the GTPase dynamin-2, impairs motor and sensory function. However, the respective contributions of muscle and nerve pathology, and the therapeutic potential of increasing DNM2 expression, remain unresolved. We evaluated tissue-targeted and systemic approaches to increase DNM2 in a mouse model carrying the common K562E-CMT mutation. Muscle-specific DNM2 overexpression from embryogenesis in Dnm2^K562E/+ mice ameliorated desmin and integrin mislocalization, membrane trafficking defects, mitochondrial abnormalities, and fibrosis in skeletal muscle, resulting in improved locomotor coordination despite persistent muscle atrophy. Conversely, systemic postnatal AAV delivery of

SUBMITTER: Goret M 

PROVIDER: S-EPMC12898409 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature