Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K(+) (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2(wt/AV)) and homozygous SUR2[A478V] (SUR2(AV/AV)) CS mice. (3) Results: In SUR2(wt/AV) and SUR2(AV/AV) mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2(wt/AV), dramatically so in SUR2(AV/AV) mice; IC(50) for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10(−5) M in SUR2(wt/AV) and 8.6 ± 0.4 × 10(−6) M in WT mice and was not measurable in SUR2(AV/AV). A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2(AV/AV) mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] “knock-in” mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2(AV/AV), with atrophy and non-inflammatory edema in different skeletal muscle phenotypes.