Background Cardiac troponin is one of the most important biomarkers in cardiology. Traditionally, it has represented a biochemical sign of necrosis, a characteristic of acute myocardial infarction (AMI). However, with the arrival of high-sensitivity detection assays, cardiac troponin is now detected in healthy people and in a number of uncommon scenarios unrelated to AMI (such as strenuous exercise, rapid atrial pacing and COVID-19). This suggest that troponin could be released as a consequence of alternative processes other than the well-stablished necrotic cell death. To try to explain this phenomenon, multiple mechanisms of troponin release have been postulated, although there is still no consensus on this matter. Furthermore, the term myocardial injury was included in the Fourth Universal Definition of Myocardial Infarction. This entity is understood as a troponin determination above the upper reference limit, not necessarily associated with a specific diagnosis. Nonetheless, the histological or pathobiological process responsible of myocardial injury has not been determined. Here, we studied the possibility of troponin release through non-classical secretion, a pathway specially triggered by cellular stress and inflammation. Methods The protein sequences of the eight different isoforms of troponin (I, T and C of fast-twitch skeletal, slow-twitch skeletal and cardiac muscle) were retrieved from the UniProtKB database. SecretomeP 2.0, a neural networks-based program, was used to predict if any of these proteins undergoes non-classical release. SignalP 5.0 and TMHMM 2.0 were also applied to rule out the possibility of classical (endoplasmic reticulum/Golgi dependent) and Type IV (transmembrane) non-classical secretion. Results and Discussion After analyzing the sequences, the cardiac T isoform was predicted to be non-classically secreted, as well as the I, T and C subunits of the fast-twitch skeletal muscle and the I subunit of the slow-twitch skeletal muscle. Additionally, none of the troponin isoforms was found to be subject to classical or Type IV secretion. The present study provides in silico evidence of cardiac troponin T release by means of non-classical secretion. We believe that this potential new mechanism could contribute to the debate around cardiac troponin high-sensitivity assays. Thus, it might establish a theoretical frame capable of explaining troponin elevations by causes other than myocyte necrosis. Conclusions Troponin T secretion may help in the pathobiological definition of myocardial injury. There are already some experimental studies showing the release of troponin through extracellular microvesicles (a type of non-classical secretion) in various cell lines. Nonetheless, more work is needed to fully understand this intriguing phenomenon in cardiomyocytes.
In silico evidence of cardiac troponin non-classical secretion: new insights on the pathobiology of myocardial injury