| First Author | Lee CS | Year | 2023 |
| Journal | Commun Biol | Volume | 6 |
| Issue | 1 | Pages | 942 |
| PubMed ID | 37709832 | Mgi Jnum | J:340280 |
| Mgi Id | MGI:7527031 | Doi | 10.1038/s42003-023-05330-y |
| Citation | Lee CS, et al. (2023) Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads. Commun Biol 6(1):942 |
| abstractText | Here we show that striated muscle preferentially expressed protein kinase alpha (Spegalpha) maintains cardiac function in hearts with Spegbeta deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegbeta but Spegalpha is expressed at ~50% of normal levels. Mice deficient in both Spegalpha and Speg beta (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegalpha in HA-Speg mice suppresses Ca(2+) leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it's low levels, HA-Spegbeta immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegbeta binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegalpha and Spegbeta display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy. |
