Excitation-Contraction Coupling Disruption in a Mouse Model of Niemann-Pick Disease

Niemann-Pick disease (NPD) is a lysosomal storage disorder that results from deficient acid sphingomyelinase (ASM) activity. It was recently proposed that ASM and extracellular Ca2+ are required for membrane repair. Since plasma membrane integrity is an important component of excitation-contraction coupling (E-C) and skeletal muscle force production, we hypothesized that there would be E-C coupling defects in NPD related to intracellular calcium (Ca2+) dynamics. Our results demonstrate that ASM deficient (ASM-/-) fibers have a reduced ability to withstand repetitive contractions in comparison to wild-type (WT) fibers, and fibers from ASM-/- mice exhibited lower peak tetanic Ca2+ compared to WT. Lastly, no differences in peak tetanic Ca2+ were found between ASM-/- fibers and WT fibers deprived of Ca2+. Together, these results suggest that both ASM and extracellular Ca2+ are required for optimal E-C coupling in skeletal muscle and for the ability to respond to repetitive contractions that occurs with sustained activity.