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Hauck Dissertation Final.pdf (5.09 MB)

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Mineralocorticoid Receptor Signaling in Acute and Chronic Muscle Injury

Hauck, James Spencer
http://rave.ohiolink.edu/etdc/view?acc_num=osu1565089935933727

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Duchenne muscular dystrophy is a severe childhood-onset striated muscle disease that has no cure. The current treatment for skeletal muscle weakness has substantial side-effects. We have previously shown that treatment with drugs that inactivate the mineralocorticoid receptor (MR) improves skeletal muscle function in muscular dystrophy mice. To determine if these MR antagonists work through direct mechanisms in the skeletal muscle, we conditionally knocked out the myofiber MR in muscular dystrophy mice. Genetic ablation of MR improved skeletal muscle force and reduced fibrosis in muscular dystrophy mice similar to that observed with MR antagonist drugs. Additionally, MR antagonists stabilize fragile dystrophic skeletal muscle membranes in a MR independent manner, suggesting that these drugs have many benefits for skeletal muscle in muscular dystrophy. We then evaluated previously identified candidate MR responsive genes for their role in muscular dystrophy. None of the evaluated genes appeared to be direct myofiber specific MR targets. To investigate the role of the myofiber MR in normal muscle biology, we acutely injured the skeletal muscle of myofiber MR conditional knockout mice on a wild-type background. We found for the first time that acutely injured skeletal muscle has MR hormonal regulation and genetic ablation of the MR temporarily stabilized damaged myofibers at four days after acute muscle injury. Pharmacological inhibition of the MR with MR antagonist treatment delayed normal muscle repair in acute injury, suggesting additional roles for MR in other cell types in skeletal muscle contribute to regeneration after acute injury. These results have implications for MR modulation after acute and chronic skeletal muscle injuries.
Jill Rafael-Fortney (Advisor)
Lawrence Kirschner (Committee Member)
Sharon Amacher (Committee Member)
Paul Martin (Committee Member)
212 p.
Cellular Biology; Molecular Biology; Physiology
Mineralocorticoid receptor; Duchenne muscular dystrophy; mdx; fibrosis; skeletal muscle; myofiber; mineralocorticoid receptor antagonist; conditional knockout mouse; spironolactone; muscle injury

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Citations

  • Hauck, J. S. (2019). Mineralocorticoid Receptor Signaling in Acute and Chronic Muscle Injury [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1565089935933727

    APA Style (7th edition)

  • Hauck, James. Mineralocorticoid Receptor Signaling in Acute and Chronic Muscle Injury. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1565089935933727.

    MLA Style (8th edition)

  • Hauck, James. "Mineralocorticoid Receptor Signaling in Acute and Chronic Muscle Injury." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1565089935933727

    Chicago Manual of Style (17th edition)

osu1565089935933727
349
© 2019, some rights reserved.Creative Commons License Mineralocorticoid Receptor Signaling in Acute and Chronic Muscle Injury by James Spencer Hauck is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.