Received for publication July 1, 2004.
Revised August 10, 2004.
Accepted for publication August 11, 2004.

Effects of Rapamycin on Cardiac and Skeletal Muscle Contraction and Crossbridge Cycling

Abstract

The immunosuppressant drug rapamycin attenuates the effects of many cardiac hypertrophy stimuli both in vitro and in vivo. While rapamycin's inhibition of mTOR and its associated signaling pathways is well established, it is likely that other signaling pathways are more important for some forms of cardiac hypertrophy. Considering the central role of myofilament protein mutations in familial hypertrophic cardiomyopathies, we tested the hypothesis that rapamycin's anti-hypertrophy action in the heart is due to direct effects of the drug on myofilament protein function. We found little or no effect of rapamycin (10^-8 - 10^-4 M) on maximum Ca²⁺-activated isometric force, while Ca²⁺-sensitivity was increased at some rapamycin concentrations in rabbit skeletal and cardiac, and rat cardiac muscle. At concentrations that increased Ca²⁺-sensitivity of isometric force, rapamycin reversibly inhibited kinetics of isometric tension redevelopment (k_TR) in rabbit skeletal, but not cardiac, muscle. The greatest inhibition (~50%) was at intermediate levels of Ca²⁺ activation, with less inhibition of k_TR (~15%) at maximum Ca²⁺ activation levels. Rapamycin (10^-7 M) increased F-actin sliding speed (~11%) in motility assays, but inhibited sliding at 10^-5 - 10^-4 M. These results indicate that rapamycin has a greater effect on Ca²⁺ regulatory proteins of the thin filament than on actomyosin interactions. These effects, however, are not consistent with rapamycin's anti-hypertrophic activity being mediated through direct effects on myofilament contractility.

Key words: actomyosin interaction, cardiac hypertrophy, in vitro motility, mTOR, muscle fiber mechanics, thin filament regulation

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