Journal Article

Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads

Yee, Rachel Sue Zhen, Agha, Nadia H., Jung, Sung Yun, Fleischman, Jorie D., Wehrens, Xander H. T., Lanza, Denise, Rodney, George G., Hanna, Amy D., Zhang, Pumin, Ward, Christopher S., Hong, Jin, Hurley, Ayrea E., Chang, Ting, Lagor, William R., Hamilton, Susan L., Babcock, Lyle W., Lee, Chang Seok, Clayton, Benjamin

2023

Overview

Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ 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 Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (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. Spegα in HA-Speg mice suppresses Ca 2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it’s low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ 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. A new mouse model of Spegβ deficiency shows that Spegα prevents the development of dilated cardiomyopathy and decreases atrophy and loss force generation in skeletal muscle. Speg-β interacts with Esd, Fsd2, and Cmya5 and stabilizes interactions among excitation-contraction coupling proteins in triads and dyads.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/44 / 14/34 / 631/443/592/75 / 631/45/475/2290 / 64/60 / 82/29 / 82/58 / 96/63 / Animals / Atrophy / Biology / Biomedical and Life Sciences / Cardiac muscle / Cardiomyopathy / Cardiomyopathy, Dilated / Dilated cardiomyopathy / Excitation-contraction coupling / Exons / Fibronectin / Heart / Immunoprecipitation / Intracellular Signaling Peptides and Proteins / Kinases / Leak channels / Life Sciences / Mice / Muscle Proteins / Muscle Weakness / Musculoskeletal system / Myopathy / Myosin-Light-Chain Kinase / Proteins / Proteolysis / Skeletal muscle / SpeG gene / Therapeutic targets / Tubules