C.P.7 Dynamin 2 in skeletal muscle development and diseases

Dynamins are large GTPases implicated in membrane remodeling and cytoskeletal dynamics. Heterozygous mutations in dynamin 2 (DNM2) have been linked to autosomal dominant centronuclear myopathy (ADCNM) and Charcot–Marie–Tooth peripheral neuropathy (CMT), two discrete progressive neuromuscular disorders, highlighting the importance of dynamin 2 for normal axonal and muscle maintenance. We have now identified the first homozygous mutation in a dynamin protein, DNM2, leading to a congenital syndrome associating fetal hypokinesia and early death. Patient fibroblasts displayed reduced transferrin uptake, and this mutation impacted on DNM2 in vitro membrane tubulation function. Skeletal muscles were strongly affected in these patients, as in patients with dominant ADCNM myopathy, suggesting a key role for DNM2 in this tissue. To gain insight into the function of DNM2 in skeletal muscle, we first exogenously expressed wild-type DNM2 or R465W DNM2, the most common ADCNM mutation, into adult wild-type mouse skeletal muscle by intramuscular Adeno-Associated Virus (AAV) injections. Expression of R465W DNM2 led to the development of a centronuclear myopathy phenotype with abnormal organelle positioning. In addition, expression of both constructs reduced the specific maximal muscle force, suggesting that the ADCNM disease arises from an increased DNM2 function. As adult muscles were injected, it also suggested that DNM2 has an important role in the maintenance of muscle structure. To further decipher the function of DNM2 in skeletal muscle, we created DNM2 knockout mice. Complete knockout of DNM2 in all tissues was lethal before embryonic day 12. Therefore we developed a muscle-specific knockout mouse and have characterized muscle-specific isoforms of DNM2. KO mice were viable to birth and muscle defects led to death within the first weeks of life. Taken together, we conclude DNM2 plays important roles in both development and maintenance of skeletal muscle.