Published Online
on March 30, 2009

A more recent version of this article appeared on July 1, 2009

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Original Article

Effects of Cardiac Myosin Isoform Variation on Myofilament Function and Crossbridge Kinetics in Transgenic Rabbits

Takeki Suzuki¹; Bradley M. Palmer¹; Jeanne James²; Yuan Wang¹; Zengyi Chen¹; Peter Van Buren¹; David W. Maughan¹; Jeffrey Robbins² and Martin M. LeWinter^1,3

¹ University of Vermont, Burlington, VT;
² Cincinnati Children's Hospital Medical Center, Cincinnati, OH

³ E-mail: martin.lewinter{at}vtmednet.org

Background—The left ventricles (LV) of both rabbits and humans express predominantly β-myosin heavy chain (MHC). Transgenic (TG) rabbits expressing 40% -MHC are protected against tachycardia-induced cardiomyopathy (TIC), but the normal amount of -MHC expressed in humans is only 5-7% and its functional importance is questionable. This study was undertaken to identify a myofilament-based mechanism underlying TIC protection and to extrapolate the impact of MHC isoform variation on myofilament function in human hearts.

Methods and Results—Papillary muscle strips from TG rabbits expressing 40% (TG40) and 15% -MHC (TG15) and from non-TG controls expressing ~100% β-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 ~50% higher power production in TG40 vs NTG40 (P<0.001) and ~20% higher power in TG15 vs NTG15 (P<0.05). A characteristic of acto-myosin crossbridge kinetics, the "dip" frequency, was significantly higher in TG40 vs NTG40 (0.70±0.04 vs 0.39±0.09 Hz, P<0.01) but not in TG15 vs NTG15. The calculated crossbridge time-on was also significantly shorter in TG40 (102.3±14.2 ms) vs NTG40 (175.7±19.7 ms), but not in TG15 vs NTG15.

Conclusions—The incorporation of 40% -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 TIC. Our results suggest, however, that, even when compared to the virtual absence of -MHC in the failing heart, the 5-7% -MHC content of the normal human heart has little if any functional significance.

Key Words: diastole • heart failure • myocardial contraction • myosin