@article {Schoffstall12, author = {Brenda Schoffstall and Aya Kataoka and Amanda Clark and P. Bryant Chase}, title = {Effects of Rapamycin on Cardiac and Skeletal Muscle Contraction and Crossbridge Cycling}, volume = {312}, number = {1}, pages = {12--18}, year = {2005}, doi = {10.1124/jpet.104.073445}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The immunosuppressant drug rapamycin attenuates the effects of many cardiac hypertrophy stimuli both in vitro and in vivo. Although rapamycin{\textquoteright}s inhibition of mammalian target of rapamycin 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{\textquoteright}s antihypertrophy 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{\textendash}8{\textendash}10{\textendash}4 M) on maximum Ca2+-activated isometric force, whereas 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 (kTR) in rabbit skeletal, but not cardiac, muscle. The greatest inhibition (\~{}50\%) was at intermediate levels of Ca2+ activation, with less inhibition of kTR (\~{}15\%) at maximum Ca2+ activation levels. Rapamycin (10{\textendash}7 M) increased actin filament sliding speed (\~{}11\%) in motility assays but inhibited sliding at 10{\textendash}5 to 10{\textendash}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{\textquoteright}s antihypertrophic activity being mediated through direct effects on myofilament contractility. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/312/1/12}, eprint = {https://jpet.aspetjournals.org/content/312/1/12.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }