Molecular Mechanisms

Genetically modified models of FHC elucidate the involved molecular mechanisms. Ex vivo analysis in cellular models was used to analyze the impact of exogenous mutants on sarcomeric structure and contractility. Histopathology or molecular consequences of mutations at mRNA or protein levels were assessed on human cardiac or skeletal muscle biopsies. In vitro analysis of purified mutant proteins has given insights into mechanical and enzymatic alterations of specific molecules. In vivo studies in animal models allow several measurements.

Most of the FHC gene mutations are missense mutations. The mutated proteins are stable and incorporated into the sarcomere after gene transfer in various cellular models (for review, see Ref. [10]) and present in human skeletal biopsies carrying a heterozygous mutation in the b-MyHC or a-TM genes.[11,12] Mutated proteins act as poison polypeptide and lead to FHC by a dominant negative effect on sarcomere structure and/or function.

Most of the MYBPC3 mutations result in a frameshift and may produce a C-terminal truncated protein, which is faintly accumulated in fetal rat cardiomyocytes,[13] even after infection of neonatal rat cardiomyocytes with adenovirus, in which they are degraded by the protea-some.[14] Truncated protein was not detected in myocar-dial tissue of patients carrying a frameshift MYBPC3 mutation.[15-17] Altogether, these data strongly suggested that frameshift mutations act as ''null allele'' leading to haploinsufficiency. To further elucidate this hypothesis, we developed cMyBP-C null mice by gene targeting.[18]

The heterozygous cMyBP-C-deficient mice, carrying only one functional allele, displayed asymmetric septal hypertrophy with myocardial disarray at 10-11 months of age. Therefore, these mice represent the first model with the major feature of human FHC, which is usually asymmetric hypertrophy predominantly affecting the interventricular septum.

The underlying pathophysiological mechanism by which missense and frameshift mutations cause LVH remains to be determined. The conventional concept of decreased contractility caused by mutant sarcomeric proteins, resulting in neuroendocrinal and mechanorecep-tor responses and compensatory hypertrophy, has been inconsistent with experimental and clinical data (for review, see Ref. [19]). Energy metabolism may play a key role as trigger for the development of HCM,[20] which is supported by HCM-like phenotypes caused by mutations in metabolic proteins. Patients with a MYH7, MYBPC3, or TNNT2 mutation exhibit impaired energy metabolism irrespective of the LVH degree.[21] We proposed that the link between mutation and energy depletion might be a disproportional alteration of mechanical and enzymatic properties of mutant sarcomeric proteins, which can result in inefficient ATP

utilization.[22]

Was this article helpful?

0 0
Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook


Post a comment