Article

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

Department of Medicine, Cardiology Unit, Fletcher Allen Health Care, Burlington, VT 05401, USA.
Circulation Heart Failure (Impact Factor: 5.95). 07/2009; 2(4):334-41. DOI: 10.1161/CIRCHEARTFAILURE.108.802298
Source: PubMed

ABSTRACT 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.
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.
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.

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