Troponin Structure and Function in Health and Disease

Abstract

Troponin (Tn) is a heterotrimeric protein containing three subunits (C, T, and I) with different molecular weights and distinctive functions. The subunits of Tn work cohesively to regulate the contraction and relaxation activities of striated muscles: troponin C (TnC) binds calcium (Ca2+), troponin T (TnT) interacts with tropomyosin (Tm) and anchors Tn to actin, and troponin I (TnI) inhibits the ATPase activity of the actomyosin cross-bridge and effectively blocks the myosin binding site on actin subunits. At a genetic level, there are 8 distinctive Tn genes (isoforms) which code for tissue specific, heart and skeletal muscle protein subunits: TNNI, TNN2, TNN3, TNNT1, TNNT2, TNNT3, TNNC1, and TNNC2. The gene isoforms are regulated throughout development via post-transcriptional and post-translational modifications. Genetic mutations in any of the three protein subunits could be linked to hypertrophic, dilated and restrictive cardiomyopathies. Tn release by damaged cardiomyocytes is clinically utilized as a biomarker for myocardial infarction, and its release into the serum is measured at specific times post injury for diagnostic or prognostic purposes. Current tests that measure serum Tn are fifth generation assays which have improved sensitivity and specificity compared to previous assays. However, increased serum Tn levels have been seen in chronic diseases such as Fabry disease and chronic renal disease. Therefore, it is important to remember that when clinically evaluating a patient, Tn levels are only one piece of the puzzle as patients’ history, symptoms, etc. are essential for making an accurate diagnosis.