Titin in vascular smooth muscle – from scaffold to mechanosensor

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Titin is a giant protein within the sarcomere – the main contractile unit of striated muscle. It determines the elastic properties of heart and skeletal muscle. Thus, titin mutations frequently cause heart or skeletal muscle disease that relate to its role in biomechanics, growth and metabolism.Smooth muscle cells express titin at much lower levels and until recently, there was little information on its potential functions in muscle cells that lack classical sarcomeres. After we have uncovered a role of smooth muscle titin in the uterus that relates to peristalsis and proper implantation, we have now extended our analysis to vascular smooth muscle. In the aorta, we find a truncated titin isoform as well as full-length titin. Our preliminary suggest differential contractile and elastic functions of titin in aorta versus smaller arteries.Here we will study the biomechanics of smooth muscle titin as well as its role in shaping the blood pressure curve, mechanotransduction and links to metabolism. In addition, we will dissect the expression of titin isoforms at mRNA and protein level as well as address the molecular basis of the phenotypes. This includes the use of localization proteomics as an unbiased approach to characterize the protein environment of smooth muscle titin.The proposed work has implications for the care of patients with cardiomyopathies resulting from titin mutations contributing to a vascular phenotype.