Length-Dependent Contractile Dynamics are Blunted Upon Ablation of Cardiac Myosin Binding Protein-C

Abstract

Enhanced cardiac contractile function due to increased sarcomere length (SL) is, in part, mediated by a decrease in the radial distance between myosin heads and actin. The radial disposition of myosin heads relative to actin is modulated by cardiac myosin binding protein-C (cMyBP-C), suggesting that cMyBP-C contributes to the length-dependent activation (LDA) in the myocardium. However, the precise role of cMyBP-C in modulating cardiac LDA is unclear. To determine the impact of cMyBP-C on LDA, we measured isometric force, myofilament Ca2+-sensitivity (pCa50) and length-dependent crossbridge (XB) contractile dynamics in skinned ventricular muscle fibers isolated from the hearts of wild-type (WT) and cMyBP-C knockout (KO) mice, at SL's 1.9µm or 2.1µm. Our results show that maximal force was not significantly different between KO and WT fibers. pCa50 was not significantly different between WT and KO fibers at long SL (5.82±0.02 in WT vs. 5.87±0.02 in KO), whereas pCa50 was significantly different between WT and KO fibers at short SL (5.71±0.02 in WT vs. 5.80±0.01 in KO; p<0.05). The rate of force redevelopment (ktr), measured at submaximal Ca2+-activation, was significantly accelerated at short SL in WT fibers (8.74±0.43s-1at 1.9µm vs. 5.71±0.40s-1at 2.1µm, p<0.05). Furthermore, the rates of stretch-induced XB relaxation (krel) and XB recruitment (kdf) were accelerated by 32% and 70%, respectively at short SL in WT fibers. In contrast, ktr was not significantly different between both SL's in KO fibers (8.03±0.54s-1at 1.9µm vs. 8.90±0.37s-1at 2.1µm). Furthermore, KO fibers did not exhibit length-dependent differences in krel and kdf -suggesting that LDA is severely depressed in KO fibers. Collectively, our data indicate that cMyBP-C plays a central role in modulating cardiac LDA.