Acute Reduction of Desmin Intermediate Filaments Alters Myocyte Mechanics and Excitation-Contraction Coupling

Abstract

Background: In the heart, many different cytoskeletal components play critical roles in regulating contractility and viscoelasticity. In diverse cardiomyopathy, these cytoskeletal components, specifically the intermediate filaments (IFs) are broadly upregulated. Our lab has recently found that interactions between microtubules and the IF desmin are important for the regulation of cardiomyocyte contractility (Robison et al., Science 2016).Aim and approach: We aim to elucidate the specific role of desmin via acute knockdown in adult ventricular myocytes. Desmin knockout mice have a variety of compensatory changes associated with the loss of this critical IF, making it difficult to determine what precise roles desmin plays. We have used shRNA against desmin and have examined alterations to the microtubule network, cell viscoelasticity, calcium handling and contractility.Results: Knockdown of desmin causes a potent reduction in the viscoelasticity of the adult cardiomyocyte. Moreover, contractility and EC coupling are robustly altered. Lastly, microtubule buckling changes from wavelengths associated with a sarcomeric periodicity, implying a crosslink to the sarcomere, to wavelengths of a broad distribution as well as those with lower changes in amplitude.Conclusion: Acute knockdown of desmin in isolated adult rat ventricular myocytes reveals previously unidentified structural and functional roles of this IF. Further study must be done to identify how desmin upregulation affects disease and other roles desmin may play in mechanotransduction.