Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS

ABCC9 ‐related intellectual disability and myopathy syndrome (AIMS) arises from loss‐of‐function (LoF) mutations in the ABCC9 gene, which encodes the SUR2 subunit of ATP‐sensitive potassium (K ATP ) channels. K ATP channels are found throughout the cardiovascular system and skeletal muscle and couple cellular metabolism to excitability. AIMS individuals show fatigability, muscle spasms, and cardiac dysfunction. We found reduced exercise performance in mouse models of AIMS harboring premature stop codons in ABCC9 . Given the roles of K ATP channels in all muscles, we sought to determine how myopathy arises using tissue‐selective suppression of K ATP and found that LoF in skeletal muscle, specifically, underlies myopathy. In isolated muscle, SUR2 LoF results in abnormal generation of unstimulated forces, potentially explaining painful spasms in AIMS. We sought to determine whether excessive Ca 2+ influx through Ca V 1.1 channels was responsible for myopathology but found that the Ca 2+ channel blocker verapamil unexpectedly resulted in premature death of AIMS mice and that rendering Ca V 1.1 channels nonpermeable by mutation failed to reverse pathology; results which caution against the use of calcium channel blockers in AIMS. Synopsis Loss‐of‐function (LoF) mutation of ABCC9 (SUR2) results in ABCC9‐related intellectual disability and myopathy syndrome (AIMS), characterized by fatigability, spasticity, and cramping. Genetically modified mouse models were used to study the muscle‐delimited effects of KATP LoF. Global SUR2 LoF mutant mice exhibit fatigability and the complete absence of skeletal muscle KATP channels. Skeletal muscle targeted knockdown of KATP channels, using a transgenic dominant‐negative approach, recapitulated the fatigability observed in global SUR2 LoF mice. Isolated muscle from SUR2 LoF mice exhibit increased generation of unstimulated forces during fatigue tests. Systemic administration of the calcium channel blocker verapamil did not improve fatigability and unexpectedly resulted in increased mortality specifically in SUR2 LoF mice. Rendering skeletal muscle CaV1.1 channels non‐permeable by mutation did not improve fatigability or unstimulated force generation in SUR2 LoF mice, suggesting calcium influx through this pathway did not underly pathology. Graphical Abstract Loss‐of‐function (LoF) mutation of ABCC9 (SUR2) results in ABCC9‐related intellectual disability and myopathy syndrome (AIMS), characterized by fatigability, spasticity,