| First Author | Kerrick WGL | Year | 2018 |
| Journal | PLoS One | Volume | 13 |
| Issue | 7 | Pages | e0200834 |
| PubMed ID | 30028847 | Mgi Jnum | J:264097 |
| Mgi Id | MGI:6192213 | Doi | 10.1371/journal.pone.0200834 |
| Citation | Kerrick WGL, et al. (2018) nNOS splice variants differentially regulate myofilament function but are dispensable for intracellular calcium and force transients in cardiac papillary muscles. PLoS One 13(7):e0200834 |
| abstractText | Cardiac muscle expresses three neuronal nitric oxide synthase (nNOS) splice variants: nNOSalpha, nNOSmu and nNOSbeta. The functions of these nNOS splice variants in cardiac muscle, particularly myofilament-associated nNOSbeta are unclear. To decipher cardiac nNOS splice variant function we investigated myofilament function and intracellular calcium and force transients in demembranated and intact papillary muscles from two lines of nNOS knockout mice. The first line (KN1) lacks nNOSalpha and nNOSmu. The second line (KN2) lacks active nNOSalpha, nNOSmu and nNOSbeta. Demembranated KN1 papillary muscles exhibited reduced myofilament ATPase activity (-35%) and specific force (-10%) relative to controls. Demembranated KN2 muscles exhibited a smaller decrease in myofilament ATPase activity (-21%), but a greater reduction in specific force (-26%) relative to controls. Myofilament calcium sensitivity in demembranated KN1 and KN2 papillary muscles was similar to controls. Thus, papillary muscle-expressed nNOS splice variants are necessary for control levels of myofilament ATPase activity and force generation, but dispensable for myofilament calcium sensitivity. The greater reduction in myofilament ATPase relative to specific force in KN1, but not KN2 muscle, reduced the energy cost of muscle contraction, suggesting that nNOSbeta increased the energetic efficiency of contraction in the absence of nNOSmu and nNOSalpha. Analyses of intact KN1 and KN2 papillary muscles showed that both intracellular calcium transients and their evoked force transients were similar to controls at stimulation frequencies between 1 and 3 Hz. Therefore, nNOS was dispensable for baseline excitation-contraction coupling. In summary, these data suggest that nNOS splice variants differentially regulate myofilament function, but not baseline calcium handling in papillary muscles. More importantly, they suggest that nNOSbeta is a novel modulator of myofilament function, and ultimately the energetic efficiency of cardiac papillary muscle contraction. |
