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EFFECTS OF GENETIC MANIPULATION OF PHOSPHOLAMBAN PROTEIN LEVELS ON CONTRACTILE FUNCTION AND REMODELING IN MURINE CARDIAC AND SLOW-TWITCH SKELETAL MUSCLES

SONG, QIUJING
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1100807947

Abstract Details

2004, PhD, University of Cincinnati, Medicine : Molecular, Cellular and Biochemical Pharmacology.
The major function of the sarcoplasmic reticulum (SR) in Ca 2+ homeostasis and contractility in cardiac and slow-twitch skeletal muscles is tightly regulated by the SR Ca 2+ ATPase (SERCA2a) and its crucial inhibitor phospholamban (PLN). The present dissertation investigated: 1) the role of PLN in cardiac muscle with specific emphasis on evaluation of the efficacy of PLN inhibition on contractile dysfunction and remodeling; and 2) the physiological significance of PLN in slow-twitch skeletal muscle. 1) In cardiac muscle, mounting evidence has shown depressed SR Ca 2+ cycling is a hallmark feature of failing heart. Normalization of Ca 2+ cycling by ablation or inhibition of the SERCA2a inhibitor PLN has prevented cardiac failure in experimental dilated cardiomyopathy. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of heart failure, remain unknown. We therefore tested the efficacy of PLN ablation in preventing the ventricular failure of Gαq overexpression induced cardiac hypertrophy. PLN ablation normalized the characteristically prolonged cardiomyocyte Ca 2+ transients and enhanced unloaded fractional shortening with no change in SR Ca 2+ pump abundance in the Gαq overexpressor. Despite “rescue” of cardiomyocyte mechanical function and Ca 2+ signaling, there was no parallel improvement in in vivo cardiac function. Furthermore, PLN ablation was unable to alleviate Gαq-induced hypertrophic remodeling. These findings indicated restoration of SR Ca 2+ cycling by PLN ablation was not sufficient to prevent the ventricular failure of the Gαq-induced cardiac hypertrophy. 2) In transgenic mice with PLN specific overexpression in slow-twitch skeletal muscle, the PLN protein levels and the PLN/SERCA2a ratio in transgenic soleus were comparable to those in cardiac muscle. The isometric-twitch contractile performance was significantly depressed in PLN overexpressing soleus, but isopreterenol stimulation relieved the inhibitory effects of PLN. Interestingly, PLN-overexpression was associated with considerable reduction in soleus mass and increased slow-fiber percentage. Therefore, increased PLN expression in slow-twitch skeletal muscle leads to impaired contractile function and muscle remodeling. In summary, the present dissertation revealed the importance of PLN protein level regulation in maintaining normal function and morphology of both cardiac and slow-twitch skeletal muscles in mice.
Dr. Evangelia Kranias (Advisor)
269 p.
phospholamban; cardiac function; slow-twitch skeletal muscle

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Citations

  • SONG, Q. (2004). EFFECTS OF GENETIC MANIPULATION OF PHOSPHOLAMBAN PROTEIN LEVELS ON CONTRACTILE FUNCTION AND REMODELING IN MURINE CARDIAC AND SLOW-TWITCH SKELETAL MUSCLES [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1100807947

    APA Style (7th edition)

  • SONG, QIUJING. EFFECTS OF GENETIC MANIPULATION OF PHOSPHOLAMBAN PROTEIN LEVELS ON CONTRACTILE FUNCTION AND REMODELING IN MURINE CARDIAC AND SLOW-TWITCH SKELETAL MUSCLES. 2004. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1100807947.

    MLA Style (8th edition)

  • SONG, QIUJING. "EFFECTS OF GENETIC MANIPULATION OF PHOSPHOLAMBAN PROTEIN LEVELS ON CONTRACTILE FUNCTION AND REMODELING IN MURINE CARDIAC AND SLOW-TWITCH SKELETAL MUSCLES." Doctoral dissertation, University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1100807947

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.