Abstract
Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) channel. In addition to diabetes, DEND patients present muscle weakness as one of the symptoms, and although the muscle weakness is considered to originate in the brain, the pathological effects of mutated KATP channels in skeletal muscle remain elusive. Here, we describe the local effects of the KATP channel on muscle by expressing the mutation present in the KATP channels of the DEND syndrome in the murine skeletal muscle cell line C2C12 in combination with computer simulation. The present study revealed that the DEND mutation can lead to a hyperpolarized state of the muscle cell membrane, and molecular dynamics simulations based on a recently reported high-resolution structure provide an explanation as to why the mutation reduces ATP sensitivity and reveal the changes in the local interactions between ATP molecules and the channel.
Highlights
Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) channel
We constructed an adeno-associated viral (AAV) vector and transfected the mouse myoblast cell line C2C12 with mutation in the Kir6.2 subunit (Kir6.2-R50P) which results in DEND s yndrome[17], and we investigated its effects on cell differentiation, myogenic index, myotube width, membrane potential and glucose uptake activity
There was no significant difference in muscle membrane potential between wild-type and m-V59M mice or wild-type and n-V59M mice, indicating that the gain-of-function mutation in the KATP channel does not directly affect muscle function itself
Summary
Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) channel. We constructed an adeno-associated viral (AAV) vector and transfected the mouse myoblast cell line C2C12 with mutation in the Kir6.2 subunit (Kir6.2-R50P) which results in DEND s yndrome[17], and we investigated its effects on cell differentiation, myogenic index, myotube width, membrane potential and glucose uptake activity.
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