Sarcolemmal ATP-sensitive potassium (K ATP ) channels are generated by the assembly of 4 Kir6.2 and 4 SUR2A subunits, and open in response to decreased intracellular ATP/ADP level, providing protection against muscle damage and metabolic depletion from excessive contractions. Complete loss-of-function (LOF) mutations of SUR2 subunits cause the rare ABCC9-related intellectual disability and myopathy syndrome (AIMS), characterized by heart disease, muscle weakness, and fatigue. Missense variants in the SUR2A exon that result in premature termination of SUR2A proteins, predicted to cause a partial LOF of K ATP channels, are present at a cumulative allele frequency of around 0.1% in the general population, and reported in association with dilated cardiomyopathy and ventricular fibrillation. However, the effects of these variants on skeletal muscle function have never been assessed. We have generated three CRISPR-Cas9 knockin SUR2A mouse lines carrying human-encoded truncation mutations, termed ICGV ∗ , LCGV ∗ , and KCGV ∗ after the resultant novel SUR2A C termini. Inside out recordings from Flexor Digitorum Brevis skeletal muscle fibers from homozygous mice confirmed the LOF nature of the variants. When tested on the inverted screen test, all homozygous SUR2A LOF mice manifested reduced in vivo muscle performance compared with littermate controls. In ex vivo isometric contraction experiments, isolated extensor digitorum longus muscles from homozygous SUR2A LOF mice developed increased unstimulated force during fatiguing protocols. Interestingly, ex vivo incubation of muscles with K V 7 channel agonist retigabine partially prevented the increase in unstimulated tension, suggesting a potential therapeutic approach. Our results indicate that even a partial reduction of SUR2A-dependent K ATP function in myocytes can induce a direct impairment of muscle function. The study adds to our previous report that sarcolemma SUR2-K ATP GOF can directly promote muscle fatigue, demonstrating the importance of the fine-tuned activity of sarcolemmal K ATP channels for normal muscle contraction.
Scala et al. (Sun,) studied this question.