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, 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 inmice 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 human DNM2 increased DNM2 in muscle but failed to transduce nerves and paradoxically worsened the muscle pathology, producing centronuclear myopathy-like features. These findings reveal a primary pathogenic impact of-CMT mutation within skeletal muscle, independent of nerve involvement. Collectively, they underscore that precise DNM2 dosage is critical for neuromuscular homeostasis and reveal a narrow therapeutic window for safe and effective therapeutic intervention. This paradox, in which efforts to compensate for a loss-of-function neuropathy risk inducing a gain-of-function myopathy, highlights the need for tightly controlled modulation of DNM2 activity in future therapeutic strategies.