Hypertrophic cardiomyopathy in MYBPC3 carriers in aging

Abstract

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3, underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.

Keywords: Age-related HCM; MYBPC3; alternative splicing; chaperone-mediated autophagy; nonsense-mediated decay; ubiquitin-proteosome system.

Figure 1.

Schematic diagram differentiating normal hearts from dilated and hypertrophied hearts. Cardiomyopathies occur due to genetic variations, resulting in distinct physiological and/or pathophysiological consequences. In terms of clinical manifestations, cardiomyocytes within hypertrophied hearts become enlarged and demonstrate cardiac dysfunction due to increased left ventricular wall thickness, diminished left ventricular cavity size, and altered blood flow rates. LA-Left Atrium, MV-Mitral Valve, LV-Left Ventricle, LVOTO-Left Ventricular Outflow Tract Obstruction.

Figure 2.

Structure and arrangements of myofilament protein in C-zone of cardiac sarcomere. The myofilaments within the sarcomere consist of two types: thick and thin filaments. The thick filaments are primarily composed of myosin protein. Each myosin molecule consists of a heavy chain that forms a tail and terminates with a globular head. Additionally, light chains interact with these globular heads. The giant protein titin spans across the sarcomere and is surrounded by myosin. The thin filaments are constituted by actin, forming a helical structure that interacts with the myosin globular heads. Cardiac myosin binding protein-C (MYBPC3), the cardiac paralog, is a regulatory protein that associates with actin and myosin, binding at its N-terminal and interacting with titin at its C-terminal. The thin filament protein, tropomyosin, wraps around the actin helix, and the three complex subunits of other thin filament proteins, known as cardiac troponins, namely Troponin C (TnC), Troponin T (TnT), and Troponin I (TnI), are also present.

Figure 3.

Schematic representation of MYBPC3 gene variant-associated molecular events and age-associated hallmarks triggering hypertrophic signals in cardiac muscles. The nonsense-mediated mRNA degradation, ubiquitin proteosome-mediated protein degradation, alternate splicing, protein phosphorylation, and deregulated calcium sensing are the most common events in the HCM phenotype with MYBPC3 mutations. The hallmarks of aging - namely, genomic instability, inflammation, autophagy, mitochondrial dysfunction, deregulated nutrient sensing, altered cellular senescence, protein homeostasis, and epigenetic alterations - activate aging-associated pathways in cardiac muscle cells. Both genetic mutation and aging-associated events generate pro-hypertrophic signals and induce hypertrophic phenotype affecting the cardiac muscle cell structure and function.

Figure 4.

Key regulatory pathways involved in the aging process. Extracellular signals (nutrients, growth factors) and intracellular signals (genomic instability, mitochondrial dysfunction, and oxidative stress) initiate aging-associated signaling events. Cellular glucose uptake acts through the AMPK pathway, while growth factors, insulin, and insulin-like growth factors bind to their respective receptors and transmit signals through the Ras and PI3K-AKT pathways. Similarly, intracellular oxidative stress (ROS) and DNA damage-associated stress signals activate the PI3K, NFκB, SIRT1, and FOXO pathways. These pathways, either directly or through mTORC1, modulate cellular processes (elevated inflammation, reduced cell growth and proliferation rate, and inhibition of autophagy), leading to the aging phenotype.

Figure 5.

Potential HCM and aging-associated molecular events mediate the late onset of HCM among MYBPC3 gene carriers. (A) Differential expression and enrichment of trans-acting factors in MYBPC3 cis-elements regulate MYBPC3 transcription upon aging. (B) Age-associated altered splicing mechanisms result in aberrant splice products, and (C) dysregulated mRNA degradation through nonsense-mediated pathways determines the abundance of MYBPC3 mRNA available for translation. (D) Aging-induced differences in the expression of miRNAs might modulate MYBPC3 translation through post-transcriptional gene silencing. (E) Age-dependent changes in phosphorylation, (F) ubiquitination proteasome system, (G) and chaperone-mediated autophagy determine the sufficiency of MYBPC3 protein in preserving cardiac function (Figure Created with BioRender.com).