Points of the molecular pathogenesis of hypertrophic cardiomyopathy associated with TRIM63 mutations

Background. The protein MuRF1 is encoded by the TRIM63 gene and is a component of the ubiquitin-proteasome protein degradation system in cardiomyocytes. Recently, an autosomal recessive form of hypertrophic cardiomyopathy (HCM) has been identified in the context of mutations in TRIM63 [1]. Currently, there are no studies utilizing cardiogenically differentiated induced pluripotent stem cellderived cardiomyocytes (iPSC-CMs) that focus on TRIM63 mutations.

Objective. To identify potential nexus in the molecular pathogenesis of cardiomyopathy associated with the TRIM63 mutation.

 Patients and methods. Experiments were conducted on cardiomyocytes differentiated from induced pluripotent stem cells (iPSCs) obtained from a 19-year-old patient with HCM due to compound-heterozygous TRIM63 variants (C39G и S161CfsTer8) [2]. The study of calcium dynamics was conducted under conditions of electrical and chemical stimulation using the fluorescent probes Fura-2AM and Fluo-4AM.

Results. During electrical stimulation of iPSC-derived cardiomyocytes with the TRIM63 mutation, a 57% increase in the calcium transient duration was observed, accompanied by a 27% reduction in calcium release rate compared to donor cardiomyocytes. The peak release rate was reached significantly later than in healthy cells. Additionally, a significant increase in calcium influx amplitude due to storeoperated entry was noted, showing a 67% enhancement.

Conclusion. In the context of TRIM63-associated hypertrophic cardiomyopathy, alterations in physiologically important cellular processes were observed. The increase in the time to reach peak calcium release rate may indicate a delay in calcium release from the sarcoplasmic reticulum, as evidenced by the parameter measuring the time to 10% of the peak. It is suggested that the sarcoplasmic reticulum exhibits unregulated calcium uptake, its retention, and consequently, calcium overload.

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