Impact of β-myosin heavy chain isoform expression on cross-bridge cycling kinetics

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Abstract
Myosin heavy chain (MHC) isoforms α and β have intrinsically different ATP hydrolysis activities (ATPase) and therefore cross-bridge cycling rates in solution. There is considerable evidence of altered MHC expression in rodent cardiac disease models; however, the effect of incremental β-MHC expression over a wide range on the rate of high-strain, isometric cross-bridge cycling is yet to be ascertained. We treated male rats with 6-propyl-2-thiouracil (PTU; 0.8 g/l in drinking water) for short intervals (6, 11, 16, and 21 days) to generate cardiac MHC patterns in transition from predominantly α-MHC to predominantly β-MHC. Steady-state calcium-dependent tension development and tension-dependent ATP consumption (tension cost; proportional to cross-bridge cycling) were measured in chemically permeabilized (skinned) right ventricular muscles at 20°C. To assess dynamic cross-bridge cycling kinetics, the rate of force redevelopment ( k tr) was determined after rapid release-restretch of fully activated muscles. MHC isoform content in each experimental muscle was measured by SDS-PAGE and densitometry. α-MHC content decreased significantly and progressively with length of PTU treatment [68 ± 5%, 58 ± 4%, 37 ± 4%, and 27 ± 6% for 6, 11, 16, and 21 days, respectively; P < 0.001 (ANOVA)]. Tension cost decreased, linearly, with decreased α-MHC content [6.7 ± 0.4, 5.6 ± 0.5, 4.0 ± 0.4, and 3.9 ± 0.3 ATPase/tension for 6, 11, 16, and 21 days, respectively; P < 0.001 (ANOVA)]. Likewise, k tr was significantly and progressively depressed with length of PTU treatment [11.1 ± 0.6, 9.1 ± 0.5, 8.2 ± 0.7, and 6.2 ± 0.3 s−1 for 6, 11, 16, and 21 days, respectively; P < 0.05 (ANOVA)] Thus cross-bridge cycling, under high strain, for α-MHC is three times higher than for β-MHC. Furthermore, under isometric conditions, α-MHC and β-MHC cross bridges hydrolyze ATP independently of one another.