title: Effects of cardiac myosin isoform variation on myofilament function and crossbridge kinetics in transgenic rabbits.
abstract: BACKGROUND
  The left ventricles of both rabbits and humans express predominantly beta-myosin heavy chain (MHC). Transgenic (TG) rabbits expressing 40% alpha-MHC are protected against tachycardia-induced cardiomyopathy, but the normal amount of alpha-MHC expressed in humans is only 5% to 7% and its functional importance is questionable. This study was undertaken to identify a myofilament-based mechanism underlying tachycardia-induced cardiomyopathy protection and to extrapolate the impact of MHC isoform variation on myofilament function in human hearts.
  
  
  RESULTS
  Papillary muscle strips from TG rabbits expressing 40% (TG40) and 15% alpha-MHC (TG15) and from nontransgenic (NTG) controls expressing approximately 100% beta-MHC (NTG40 and NTG15) were demembranated and calcium activated. Myofilament tension and calcium sensitivity were similar in TGs and respective NTGs. Force-clamp measurements revealed approximately 50% higher power production in TG40 versus NTG40 (P<0.001) and approximately 20% higher power in TG15 versus NTG15 (P<0.05). A characteristic of acto-myosin crossbridge kinetics, the "dip" frequency, was significantly higher in TG40 versus NTG40 (0.70+/-0.04 versus 0.39+/-0.09 Hz, P<0.01) but not in TG15 versus NTG15. The calculated crossbridge time-on was also significantly shorter in TG40 (102.3+/-14.2 ms) versus NTG40 (175.7+/-19.7 ms) but not in TG15 versus NTG15.
  
  
  CONCLUSIONS
  The incorporation of 40% alpha-MHC leads to greater myofilament power production and more rapid crossbridge cycling, which facilitate ejection and relengthening during short cycle intervals, and thus protect against tachycardia-induced cardiomyopathy. Our results suggest, however, that, even when compared with the virtual absence of alpha-MHC in the failing heart, the 5% to 7% alpha-MHC content of the normal human heart has little if any functional significance.
authors.affiliation: Department of Medicine, Cardiology Unit, Fletcher Allen Health Care, Burlington, VT 05401, USA.
authors.forename: Takeki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Palmer
authors.forename: Jeanne
authors.initials: J
authors.lastname: James
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zengyi
authors.initials: Z
authors.lastname: Chen
authors.forename: Peter
authors.initials: P
authors.lastname: VanBuren
authors.forename: David W
authors.initials: DW
authors.lastname: Maughan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Martin M
authors.initials: MM
authors.lastname: LeWinter
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D018995:Myosin Heavy Chains / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D011817:Rabbits; D013610:Tachycardia / Q000150:complications
chemical_list: D020033:Protein Isoforms; D018995:Myosin Heavy Chains