Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development

Abstract

Familial hypertrophic cardiomyopathy (FHC) is the most frequent inherited cardiac disease. It has been related to numerous mutations in many sarcomeric and even some non-sarcomeric proteins. So far, however, no common mechanism has been identified by which the many different mutations in different sarcomeric and non-sarcomeric proteins trigger development of the FHC phenotype. Here we show for different MYH7 mutations variance in force pCa-relations from normal to highly abnormal as a feature common to all mutations we studied, while direct functional effects of the different FHC-mutations, e.g., on force generation, ATPase or calcium sensitivity of the contractile system, can be quite different. The functional variation among individual M. soleus fibers of FHC-patients is accompanied by large variation in mutant vs. wildtype β-MyHC-mRNA. Preliminary results show a similar variation in mutant vs. wildtype β-MyHC-mRNA among individual cardiomyocytes. We discuss our previously proposed concept as to how different mutations in the β-MyHC and possibly other sarcomeric and non-sarcomeric proteins may initiate an FHC-phenotype by functional variation among individual cardiomyocytes that results in structural distortions within the myocardium, leading to cellular and myofibrillar disarray. In addition, distortions can activate stretch-sensitive signaling in cardiomyocytes and non-myocyte cells which is known to induce cardiac remodeling with interstitial fibrosis and hypertrophy. Such a mechanism will have major implications for therapeutic strategies to prevent FHC-development, e.g., by reducing functional imbalances among individual cardiomyocytes or by inhibition of their triggering of signaling paths initiating remodeling. Targeting increased or decreased contractile function would require selective targeting of mutant or wildtype protein to reduce functional imbalances.

Variable cardiac myosin binding protein-C expression in the myofilaments due to MYBPC3 mutations in hypertrophic cardiomyopathy

“…This burst-like, stochastic on/off-switching of allele transcription should average out over time, but in case of heterozygosity with protein product of different stability, it can lead to variable expression of healthy and mutant proteins. This was recently shown by Kraft and colleagues [6,7]. Patients with heterozygous HCM-associated MYH7 gene mutation demonstrated a variable healthy:mutant ratio of mRNA expression in cardiomyocytes from the same heart [6].…”

Mechanical parameters of the molecular motor myosin II determined in permeabilised fibres from slow and fast skeletal muscles of the rabbit

“…; Brenner et al . ). In slow fibres from soleus muscle of human, it has been found that a single natural mutation occurring in the converter domain (708–780 region) of the slow β‐MHC isoform is responsible for a large change in motor stiffness.…”

Converter domain mutations in myosin alter structural kinetics and motor function

“…It was previously determined that mutations in the converter domain can impair the stiffness of a myosin head and thus alter its force-generating properties without altering cross-bridge kinetics (41)(42)(43). Studies of the R723G mutation in human M2␤, which corresponds to R712G in MV, found an increase in the rigidity of the strongly bound myosin heads, which led to a 1.3-fold increase in force per myosin head (43).…”