Faster Cross-Bridge Relaxation Rates Correlate with Increased Tension Cost in Hcm with the R403Q Myh7 Mutation

Abstract

The first mutation found to be associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain. R403Q is located in the globular head of myosin (S1), responsible for actin interaction, and hence motor function of myosin. According to the 2-state model of actin-myosin interaction total cross-bridge turnover rate can be described by the sum of the cross-bridge association (fapp) and detachment (gapp) rates. Gapp is equivalent to the slow rate of cross-bridge relaxation (slow krel), which equals the energetic cost of tension generation, i.e. tension cost (expressed by ATP utilization/tension). In the present study we investigated to what extent cross-bridge kinetics in HCM with the R403Q mutation correlated with cross-bridge energetics.Left ventricular multicellular muscle strips and myofibrillar preparations were isolated from 3 HCM patients with the R403Q mutation. 8 HCM sarcomere mutation negative (HCMsmn) patients served as control. In the muscle strips force generating capacity and ATP utilization were measured to assess tension cost and in the myofibrillar preparations cross-bridge kinetics was analyzed. The fraction of mutated R403Q mRNA was analyzed using specific restriction digests and realtime-PCR. Compared to HCMsmn tension cost was higher in the muscle strips of the 3 R403Q patients which showed a positive linear correlation with relaxation kinetics in the corresponding myofibrillar preparations. Variation in cross-bridge function among the 3 R403Q patients could not be explained by differences in R403Q mRNA levels.Cross-bridge cycling efficiency was decreased in HCM due to the R403Q mutation, while cross-bridge kinetics was increased. This suggests that the apparent gain in function evident from increased kinetics leads to a loss of function with respect to cross-bridge cycling efficiency in HCM caused by the R403Q mutation.