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Uncovering the complexity of muscular dystrophy pathology through disease signaling

Wissing, Erin R
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1393236115

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
The muscular dystrophies (MD) are a diverse group of inherited disorders best characterized by muscle wasting. Progressive weakening and wasting of skeletal muscle leads to loss of ambulation in the teen years and premature death in the second or third decade of life. Many of the MDs are caused by mutations in proteins in the dystrophin glycoprotein complex (DGC). In the absence of a functioning DGC, the sarcolemma becomes unstable during contraction and microtears occur allowing an unregulated influx of ions, such as Ca2+ , to enter the myofiber leading to the induction of multiple signaling or cellular pathways. Here we present data from three different pathways in skeletal muscle in an effort to shed more light on the complex and multifaceted MDs, and identify targets for future therapeutics in dystrophic patients. First we show that the potent cyclophilin D (Cyp D) and mitochondrial permeability transition pore (MPTP) inhibitor, Debio-025, can work in combination with prednisone with no adverse effects in mdx mice. Here we find that treatment of mdx mice with Debio-025 by oral gavage or subcutaneous injection alone or in combination with prednisone significantly decreases pathology compared to vehicle controls. However, the combination treatment of Debio-25 and prednisone is not additive, indicating that Debio-025 and prednisone could be working through similar pathways. Thus, we found that co-administration with prednisone had no adverse side effects. The p38 MAPK signal amplification cascade is known to play roles in many cellular processes; however, no definitive link to dystrophy has been described. Here we present data suggesting p38a as a potent signaling effector which promotes disease progression in MD through a cell death dependent mechanism. To test this hypothesis we crossed p38a skeletal muscle specific knockdown mice to d-sarcoglycan (Sgcd-/-) and mdx mice and found that the loss of p38a alleviated pathology. Muscle specific over-activation of MKK6-p38 activity was found to produce a severe dystrophic-like muscle wasting pathology, indicating that p38 MAPK is sufficient to cause disease in skeletal muscle due to p38 specific phosphorylation of the cell death protein Bax (T167). Treatment of Sgcd-/- mice with a p38 inhibitor was also found to reduce disease. Finally, the ERK1/2 MAPK pathway has been shown to play a role in many cellular processes including skeletal muscle fiber type determination. In dystrophic muscle, the fast fibers are affected first, due to their high contraction speed and force production. In our preliminary studies, we find that skeletal muscle specific over-activation of ERK1/2 MAPK produces a slow fiber-type phenotype in transgenic mice, indicating a role for ERK1/2 in slow twitch fiber preservation. This indicates that ERK1/2 over-activation could be protective in dystrophic mice due to a promotion of slower muscle phenotype. Our studies have shown in mice that Debio-025 can work in combination with prednisone to decrease pathology, p38a promotes disease pathology, and ERK1/2 over-activation causes a protective fiber type switch. Taken together these studies suggest multiple therapeutic targets that could be used to treat MD.
Jeff Molkentin, Ph.D. (Committee Chair)
James Lessard, Ph.D. (Committee Member)
Jerry Lingrel, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
David Wieczorek, Ph.D. (Committee Member)
147 p.
Molecular Biology
p38 MAPK; Muscular dystrophy; cell death; Debio 025; p38 inhibitor; ERK1 2

Recommended Citations

Citations

  • Wissing, E. R. (2014). Uncovering the complexity of muscular dystrophy pathology through disease signaling [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1393236115

    APA Style (7th edition)

  • Wissing, Erin. Uncovering the complexity of muscular dystrophy pathology through disease signaling. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1393236115.

    MLA Style (8th edition)

  • Wissing, Erin. "Uncovering the complexity of muscular dystrophy pathology through disease signaling." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1393236115

    Chicago Manual of Style (17th edition)

ucin1393236115
506
© 2014, some rights reserved.Creative Commons License Uncovering the complexity of muscular dystrophy pathology through disease signaling by Erin R Wissing 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 University of Cincinnati and OhioLINK.