QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.073445v1 312/1/12    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schoffstall, B. Articles by Chase, P. B. Search for Related Content PubMed PubMed Citation Articles by Schoffstall, B. Articles by Chase, P. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL

CARDIOVASCULAR

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

Department of Biological Science and Program in Molecular Biophysics, Florida State University, Tallahassee, Florida

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 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 (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 actin filament sliding speed (11%) in motility assays but inhibited sliding at 10^–5 to 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 antihypertrophic activity being mediated through direct effects on myofilament contractility.

Address correspondence to: Dr. P. Bryant Chase, Biology Unit One, Room 222, Florida State University, Tallahassee, FL 32306. E-mail: chase{at}bio.fsu.edu

This article has been cited by other articles:

				M. J. Drummond, C. S. Fry, E. L. Glynn, H. C. Dreyer, S. Dhanani, K. L. Timmerman, E. Volpi, and B. B. Rasmussen Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis J. Physiol., April 1, 2009; 587(7): 1535 - 1546. [Abstract] [Full Text] [PDF]

				J. A. Kuzman, T. D. O'Connell, and A. M. Gerdes Rapamycin Prevents Thyroid Hormone-Induced Cardiac Hypertrophy Endocrinology, July 1, 2007; 148(7): 3477 - 3484. [Abstract] [Full Text] [PDF]

				M. Padmasekar, R. Nandigama, M. Wartenberg, K.-D. Schluter, and H. Sauer The acute phase protein {alpha}2-macroglobulin induces rat ventricular cardiomyocyte hypertrophy via ERK1,2 and PI3-kinase/Akt pathways* Cardiovasc Res, July 1, 2007; 75(1): 118 - 128. [Abstract] [Full Text] [PDF]

				B. Schoffstall, N. M. Brunet, S. Williams, V. F. Miller, A. T. Barnes, F. Wang, L. A. Compton, L. A. McFadden, D. W. Taylor, M. Seavy, et al. Ca2+ sensitivity of regulated cardiac thin filament sliding does not depend on myosin isoform J. Physiol., December 15, 2006; 577(3): 935 - 944. [Abstract] [Full Text] [PDF]