Impact of beta-myosin heavy chain isoform expression on cross-bridge cycling kinetics.
Myosin heavy chain (MHC) isoforms alpha and beta 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 beta-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 alpha-MHC to predominantly beta-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 degrees C. To assess dynamic cross-bridge cycling kinetics, the rate of force redevelopment (ktr) was determined after rapid release-restretch of fully activated muscles. MHC isoform content in each experimental muscle was measured by SDS-PAGE and densitometry. alpha-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 alpha-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, ktr 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 alpha-MHC is three times higher than for beta-MHC. Furthermore, under isometric conditions, alpha-MHC and beta-MHC cross bridges hydrolyze ATP independently of one another.
Rundell
Veronica L M
VL
Center for Cardiovascular Research, Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Manaves
Vlasios
V
Martin
Anne F
AF
de Tombe
Pieter P
PP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D007037:Hypothyroidism / Q000378:metabolism* / Q000503:physiopathology; D007536:Isomerism; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000378:metabolism*; D011441:Propylthiouracil / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D024723:Ventricular Myosins / Q000737:chemistry / Q000378:metabolism
D013956:Antithyroid Agents; C000594638:MYH7 protein, rat; D011441:Propylthiouracil; D000255:Adenosine Triphosphate; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains