Abstract
Dynamic movements of the cardiac troponin complex are an important component of the cardiac cycle. Whether cardiac troponins are subjected to irreversible advanced glycation end-product (AGE) modification is unknown. This study interrogated human and rat cardiac troponin-C, troponin-I and troponin-T to identify endogenous AGE modifications using mass spectrometry (LC-MS/MS). AGE modifications were detected on two amino acid residues of human troponin-C (Lys6, Lys39), thirteen troponin-I residues (Lys36, Lys50, Lys58, Arg79, Lys117, Lys120, Lys131, Arg148, Arg162, Lys164, Lys183, Lys193, Arg204), and three troponin-T residues (Lys107, Lys125, Lys227). AGE modifications of three corresponding troponin-I residues (Lys58, Lys120, Lys194) and two corresponding troponin-T residues (Lys107, Lys227) were confirmed in cardiac tissue extracts from an experimental rodent diabetic model. Additionally, novel human troponin-I phosphorylation sites were detected (Thr119, Thr123). Accelerated AGE modification of troponin-C was evident in vitro with hexose sugar exposure. This study provides the first demonstration of the occurrence of cardiac troponin complex AGE-modifications. These irreversible AGE modifications are situated in regions of the troponin complex known to be important in myofilament relaxation, and may be of particular pathological importance in the pro-glycation environment of diabetic cardiomyopathy.
Highlights
Dynamic movements of the cardiac troponin complex are an important component of the cardiac cycle
This study provides the first evidence that all subunits of the human cardiac troponin complex are modified by endogenous advanced glycation end-product (AGE) formation
This approach may produce an AGE ‘under-detection’ bias, the extent of which can only be determined by further investigation. These considerations highlight the imperative for further exploration of the role of troponin AGE-modification in myocardial pathophysiology. This is the first study to demonstrate that all three human cardiac troponin subunits can exhibit AGE modification
Summary
Dynamic movements of the cardiac troponin complex are an important component of the cardiac cycle. This study provides the first demonstration of the occurrence of cardiac troponin complex AGE-modifications These irreversible AGE modifications are situated in regions of the troponin complex known to be important in myofilament relaxation, and may be of particular pathological importance in the pro-glycation environment of diabetic cardiomyopathy. Troponin mutations are detected in many inherited cardiomyopathies[15], providing evidence that small changes in the troponin protein sequence may have major implications for cardiac function. Both Ca2+ sensitizing and Ca2+ desensitizing troponin mutations have been identified, associated with either a hypertrophic/restrictive cardiomyopathy or a dilated cardiomyopathy phenotype respectively[15]. Extracellular AGE-crosslinking of myocardial collagen is well-described[24], few studies have investigated the role of AGE formation on intracellular proteins
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