Effects of rapamycin on cardiac and skeletal muscle contraction and crossbridge cycling.
The immunosuppressant drug rapamycin attenuates the effects of many cardiac hypertrophy stimuli both in vitro and in vivo. Although rapamycin'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'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(-8)-10(-4) M) on maximum Ca(2+)-activated isometric force, whereas Ca(2+) sensitivity was increased at some rapamycin concentrations in rabbit skeletal and cardiac and rat cardiac muscle. At concentrations that increased Ca(2+) sensitivity of isometric force, rapamycin reversibly inhibited kinetics of isometric tension redevelopment (k(TR)) in rabbit skeletal, but not cardiac, muscle. The greatest inhibition (approximately 50%) was at intermediate levels of Ca(2+) activation, with less inhibition of k(TR) (approximately 15%) at maximum Ca(2+) activation levels. Rapamycin (10(-7) M) increased actin filament sliding speed (approximately 11%) in motility assays but inhibited sliding at 10(-5) to 10(-4) M. These results indicate that rapamycin has a greater effect on Ca(2+) regulatory proteins of the thin filament than on actomyosin interactions. These effects, however, are not consistent with rapamycin's antihypertrophic activity being mediated through direct effects on myofilament contractility.
Department of Biological Science and Program in Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
Brenda
B
Schoffstall
Aya
A
Kataoka
Amanda
A
Clark
P Bryant
PB
Chase
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000205:Actomyosin; D002118:Calcium; D020123:Sirolimus