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Calcium cycling and contractile activation in intact mouse cardiac muscle

Wei Dong Gao, Nestor Gustavo Perez and Eduardo Marban

1. Excitation-contraction coupling in mouse cardiac muscle remains poorly characterized, despite the fact that the mouse is the mammalian species of choice for genetic manipulation. In this study, we characterized the relationship between internal calcium concentration ([Ca²⁺]_i) and contraction in intact mouse ventricular muscle loaded with fura-2 salt at 20-22 °C.

2. Both Ca²⁺ transient amplitude and twitch force increased monotonically as external Ca²⁺ concentration ([Ca²⁺]_o) was increased up to 8·0 mM, with no changes in diastolic levels or in the times to peak of either Ca²⁺ transients or force. The decay of Ca²⁺ transients was accelerated as [Ca²⁺]_o increased, while relaxation was prolonged. Both Ca²⁺ transient amplitude and twitch force increased as stimulation rate increased from 0·2 to 4 Hz, but the increase in force was much greater than the underlying increase in [Ca²⁺]_i.

3. The steady-state force-[Ca²⁺]_i relationship revealed an [Ca²⁺]_i required for 50 % of maximal activation (Ca₅₀) of 0·95 ± 0·08 µM, a Hill coefficient of 9·9 ± 2·6, and a maximal Ca²⁺-activated force (F_max) of 60 ± 5 mN mm^-2.

4. Unlike rat ventricular myocardium, mouse cardiac muscle resists supraphysiological [Ca²⁺]_o. The strong positive force-frequency relationship in mouse cardiac muscle, with increases of force disproportionate to the increases in Ca²⁺ transients, suggests frequency-dependent 'sensitization' of the myofilaments. During steady-state activation, mouse muscle exhibits decreased Ca²⁺ responsiveness relative to other species, but high co-operativity.

5. These physiological features of mouse cardiac muscle merit consideration when interpreting the phenotypic consequences of genetic manipulations

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