Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1078511890.pdf (1.75 MB)

ETD Abstract Container

Abstract Header

THE ROLE OF CALCINEURIN IN SKELETAL MUSCLE HYPERTROPHY AND FIBER TYPE DIVERSITY

PARSONS, STEPHANIE A
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078511890

Abstract Details

2004, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry and Microbiology.
Calcineurin is a calcium-regulated serine-threonine protein phosphatase that controls developmental and inducible biological responses in diverse cell types, in part through activation of the transcription factors nuclear factor of activated T cells (NFAT) and myocyte enhancer binding factor 2 (MEF2). In skeletal muscle, calcineurin has been implicated in the regulation of myoblast differentiation, myofiber hypertrophy, and fiber-type switching in response to alterations in intracellular calcium concentration. However, considerable disagreement persists regarding the functional role of calcineurin signaling these processes. Here, we evaluated the molecular phenotypes of skeletal muscle from calcineurin-deficient mice, including calcineurin Aalpha-/-, calcineurin Abeta-/-, and calcineurin B1 LoxP/LoxP mice expressing cre recombinase specifically in skeletal muscle. Calcineurin expression appears to be important during early myogenesis in establishment of fiber number in some muscles. We also found that calcineurin Aalpha-/- and Abeta-/- mice exhibit overall growth defects, and calcineurin Abeta-/- mice have smaller relative muscle weights. These defects were not seen, however, in calcineurin B1 LoxP MLC-cre mice, in which calcineurin is down-regulated at embryonic day 12.5, indicating that these defects originate from early myogenic events. Decreased levels of calcineurin expression also inhibited the establishment of slow/oxidative fibers. This decrease in some cases occurred without any change in the nuclear occupancy of NFAT proteins, suggesting that NFATs are not involved in the initial establishment of fiber type. Loss of calcineurin expression did not affect muscle growth following IGF-1/GH administration or mechanical overload. NFAT-luciferase reporter mice, used to analyze calcineurin activity, displayed no change in activity after IGF-1/GH administration but exhibited a dramatic increase following overload, which correlated with increased NFATc1 protein expression in all mice except calcineurin B flox/flox MLC-cre. Calcineurin B flox/flox MLC-cre mice also did not undergo the normal fast-to-slow fiber type switching that normally occurs during hypertrophy. Collectively, our results indicate that calcineurin has two important roles during development, in establishment of fiber number and in mediating the slow-twitch phenotype. In adult skeletal muscle, loss of calcineurin expression negatively impacts the relative fiber number of skeletal muscle and the ability to undergo fiber type switching in response to overload, but does not affect muscle growth in response to hypertrophic stimuli.
Dr. Jeffery Molkentin (Advisor)
142 p.
Biology, Molecular
calcineurin; skeletal muscle; hypertrophy; NFAT; overload; myosin heavy chain

Recommended Citations

Citations

  • PARSONS, S. A. (2004). THE ROLE OF CALCINEURIN IN SKELETAL MUSCLE HYPERTROPHY AND FIBER TYPE DIVERSITY [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078511890

    APA Style (7th edition)

  • PARSONS, STEPHANIE. THE ROLE OF CALCINEURIN IN SKELETAL MUSCLE HYPERTROPHY AND FIBER TYPE DIVERSITY. 2004. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078511890.

    MLA Style (8th edition)

  • PARSONS, STEPHANIE. "THE ROLE OF CALCINEURIN IN SKELETAL MUSCLE HYPERTROPHY AND FIBER TYPE DIVERSITY." Doctoral dissertation, University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1078511890

    Chicago Manual of Style (17th edition)

ucin1078511890
942
© 2004, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.