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Attenuation of length dependence of calcium activation in myofilaments of transgenic mouse hearts expressing slow skeletal troponin I

Grace M. Arteaga*, Kimberly A. Palmiter *, Jeffrey M. Leiden † and R. John Solaro *

1. We compared sarcomere length (SL) dependence of the Ca²⁺-force relation of detergent-extracted bundles of fibres dissected from the left ventricle of wild-type (WT) and transgenic mouse hearts expressing slow skeletal troponin I (ssTnI-TG). Fibre bundles from the hearts of the ssTnI-TG demonstrated a complete replacement of the cardiac troponin I (cTnI) by ssTnI.

2. Compared to WT controls, ssTnI-TG fibre bundles were more sensitive to Ca²⁺ at both short SL (1·9 ± 0·1 µm) and long SL (2·3 ± 0·1 µm). However, compared to WT controls, the increase in Ca²⁺ sensitivity (change in half-maximally activating free Ca²⁺; EC₅₀) associated with the increase in SL was significantly blunted in the ssTnI-TG myofilaments.

3. Agents that sensitize the myofilaments to Ca²⁺ by promoting the actin-myosin reaction (EMD 57033 and CGP-48506) significantly reduced the length-dependent EC₅₀ for Ca²⁺ activation, when SL in WT myofilaments was increased from 1·9 to 2·3 µm.

4. Exposure of myofilaments to calmidazolium (CDZ), which binds to cTnC and increases its affinity for Ca²⁺, sensitized force developed by WT myofilaments to Ca²⁺ at SL 1·9 µm and desensitized the WT myofilaments at SL 2·3 µm. There were no significant effects of CDZ on ssTnI-TG myofilaments at either SL.

5. Our results indicate that length-dependent Ca²⁺ activation is modified by specific changes in thin filament proteins and by agents that promote the actin-myosin interaction. Thus, these in vitro results provide a basis for using these models to test the relative significance of the length dependence of activation in situ.

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