Abstract
Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. αII spectrin (SPTAN1) is one of two α spectrin genes and αII spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability. Furthermore, human αII spectrin loss-of-function variants cause neurological disease. As global αII spectrin knockout mice are embryonic lethal, the in vivo roles of αII spectrin in adult heart are unknown and untested. Here, based on pronounced alterations in αII spectrin regulation in human heart failure we tested the in vivo roles of αII spectrin in the vertebrate heart. We created a mouse model of cardiomyocyte-selective αII spectrin-deficiency (cKO) and used this model to define the roles of αII spectrin in cardiac function. αII spectrin cKO mice displayed significant structural, cellular, and electrical phenotypes that resulted in accelerated structural remodeling, fibrosis, arrhythmia, and mortality in response to stress. At the molecular level, we demonstrate that αII spectrin plays a nodal role for global cardiac spectrin regulation, as αII spectrin cKO hearts exhibited remodeling of αI spectrin and altered β-spectrin expression and localization. At the cellular level, αII spectrin deficiency resulted in altered expression, targeting, and regulation of cardiac ion channels NaV1.5 and KV4.3. In summary, our findings define critical and unexpected roles for the multifunctional αII spectrin protein in the heart. Furthermore, our work provides a new in vivo animal model to study the roles of αII spectrin in the cardiomyocyte.
Highlights
Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. ␣II spectrin (SPTAN1) is one of two ␣ spectrin genes and ␣II spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability
In the heart alone, defects in myocyte cytoskeletal proteins have been linked with a host of structural and electrical phenotypes in human cardiovascular disease as well as in animal disease models (4)
Based on the critical role of spectrins in excitable cells and dysregulation in heart failure (Fig. 1), we investigated the role of ␣II spectrin for in vivo cardiac function
Summary
To evaluate potential dysregulation of ␣II spectrin in human cardiovascular disease, we performed immunoblot experiments on failing and nonfailing human left ventricle. We observed a statistically significant increase in action potential amplitude (APA) in ␣II spectrin cKO myocytes compared with control cells (Fig. S7D). In further support of a role for ␣II spectrin in potassium channel regulation, we observed a significant increase in protein expression of KV4.3 (Fig. 9, A and B). Established markers of cardiac hypertrophy were significantly altered, foreshadowing the increased cardiomyocyte size observed in older (20 –24 –weekold) mice (Fig. S13) We hypothesize that these changes serve to augment and/or accelerate phenotypes in ␣II spectrin cKO mice. Increased vacuolization of cardiac tissue was observed in ␣II spectrin cKO mice but not control mice (Fig. S14, B, C, E, and F) These changes occur in the absence of generalized disruption of the cardiomyocyte sarcomere or intercalated disc structure (Fig. S16). ␣II spectrin is required for normal physiologic cardiac remodeling, as loss of ␣II spectrin results in accelerated heart failure phenotypes in response to standard experimental models of heart failure and hypertrophy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
