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  • We also found downregulation of TRIM in


    We also found downregulation of TRIM32 in the hearts of dilated and hypertrophic cardiomyopathy patients in addition to TAC and phenylephrine treated mice [51]. TRIM32 and Dysbindin are known to interact in skeletal muscle, and we could confirm this interaction in cardiomyocytes as well. In cardiomyocytes, we found that by means of degradation, TRIM32 diminished the pro-hypertrophic effects of Dysbindin. Furthermore, we also found that TRIM32 protect apoptotic inducer p53 and degrades apoptotic inhibitor XIAP through upregulation of Caspase3 and Caspase7, thereby critically affecting cellular viability. Thus, we caution against putting TRIM32 forward as a therapeutic agent for cardiac hypertrophy, as this approach may have unwanted side effects due to increased apoptosis and reduced cell viability.
    TRIM72 (MG53) TRIM72, also known as Mitsugumin53 (MG53), possesses the most common structure of TRIM family members, with RING-Bbox1-Coiled coil-PRY/SPRY domains conservatively aligned from N-terminus to C-terminus. Mammalian Gene Collection (MGC) indicates two possible mammalian isoforms of TRIM72, one of which has been stated canonical and studied intensively in the context of preserving muscle integrity by sarcomere repair in skeletal and cardiac muscles [75]. MG53 is noted to play a central role in insulin resistance and thus metabolic disorders such as obesity and diabetes, with possible involvement in cardiovascular diseases like diabetic cardiomyopathy. MG53 has been reported to mediate degradation of both insulin receptor and insulin receptor substrate 1 (IRS1), causing dyslipidemia and TG4-155 besides metabolic disorders. In contrast, its ablation has been credited with preserving insulin receptor and IRS1. Thus, the mechanistic role of MG53 has been defined by investigating it as therapeutic agent for metabolic disorders and their cardiovascular complications [76]. In the heart, MG53 has been reported to be TG4-155 a vital player in both preconditioning and post-conditioning by activating PI3K-Akt-GSK3β and ERK1/2 cell survival signaling pathways in ischemia-reperfusion [77], [78]. For example, myocardial injury resulting from ischemia/reperfusion in the dysferlin murine KO model is strongly correlated with myocardial muscle impairment, resulting in a clinical trial in pediatric patients undergoing corrective heart surgery. Notably, human myocardium does not express MG53; suggesting rhMG53 might be an effective tool for muscular injuries in both skeletal and cardiac muscle repair [79]. Furthermore, MG53 (TRIM72) has been reported with dual roles, beneficial in phosphatidylserine-dependent prevention of skeletal muscle damage, protection of heart against ischemia-reperfusion injury, protection of other vital organs by membrane repair; while being maladaptive in the development of skeletal muscle insulin resistance, in the regulation of myogenesis [80]. This ‘Janus-faced’ nature of TRIM72 makes it a double-edged-sword for human diseases, taking in question its usage as a therapeutic agent.
    Expression data suggest involvement of additional TRIMs in heart function Given the complexity of the cardiac function, involved molecular pathways and processes, and the fact that only a few of the TRIMs have thus far been shown to have a cardiac role, we hypothesized that there would be more TRIMs mediating important functions in the heart. Along these lines, we checked the expression of all known human TRIMs in various heart regions using human affymetrix data publicly available with Genevestigator ( Several of the yet uncharacterized TRIMs were found to be significantly expressed in the heart, such as TRIM18, TRIM22, TRIM42, TRIM49, TRIM67, TRIM69, and TRIM73 (Fig. 5A). We additionally determined the expression of all TRIMs present in myocardium under cardiac disease settings like heart failure, cardiomyopathies, myocardial infarction, and atrial fibrillation. Interestingly, in addition to known cardiac TRIMs, several other TRIMs were found to be differentially regulated in these disease conditions (Fig. 5B). Moreover, majority of the TRIMs which were found significantly expressed in the heart e.g. TRIM17, TRIM18, TRIM22, TRIM42, TRIM48, TRIM49, TRIM67, TRIM69, and TRIM73, were also part of the dysregulated TRIMs in cardiac disease conditions. Although these bioinformatics findings need experimental validations, overall, these data suggests the potential of more cardiac specific research for TRIMs in disease context (Fig. 5B).