Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1211297412.pdf (3.73 MB)

ETD Abstract Container

Abstract Header

Calcium as the central mediator of muscle dysfunction due to muscular dystrophy

Millay, Douglas P.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Muscular dystrophy (MD) is a debilitating genetic disorder affecting cardiac and skeletal muscle that typically results in loss of ambulation in the teen years and death in the second or third decade of life. The gene disruptions that cause this muscle wasting disease have been known for over 20 years and most encode proteins which reside in a large complex known as the dystrophin-glycoprotein complex (DGC). The function of the DGC is to provide structural support to the sarcolemma (muscle cell membrane) effectively reducing membrane damage after contraction. In the absence of a functional DGC, contraction-induced lesions in the sarcolemma occur and this is hypothesized to initiate MD disease progression. Destabilization of the membrane is proposed to cause the unregulated entry of calcium into the myofiber, possibly causing degeneration of the fiber. Despite good evidence that calcium levels are altered in dystrophic myotubes, at least in the subsarcolemmal space, there is a lack of knowledge concerning the pathways by which this intracellular calcium results in degeneration. Moreover, there are currently no studies directly implicating calcium as the disease-inducing molecule in MD. Here, we present data suggesting that mitochondria are one sensor of this increased calcium and respond by undergoing mitochondrial permeability transition (MPT) resulting in necrosis of the myofiber. To test this hypothesis we crossed animals lacking cyclophilin D (CypD, Ppif gene), a critical regulator of MPT, with two MD models. In both cases, mice lacking the extracellular matrix protein lamanin-2a (Lama2-/-) or the DGC protein δ-sarcoglycan (Scgd-/-) along with Ppif exhibited a reduction in disease characteristics compared to the same animals with normal levels of CypD. Specifically, mitochondria from muscle of the MD mice were swollen and genetic loss of Ppif rescued this phenotype, inhibiting MPT and ultimately reducing disease through a mitochondrial-dependent mechanism. This led us to test the efficacy of a CypD inhibitor, Debio-025, in its ability to block MPT and attenuate disease progression. Indeed, Scgd-/- and mdx (mouse model lacking dystrophin) mice treated with Debio-025 for 6 weeks showed a lessening of disease characteristics compared to vehicle-treated controls. Thus, MPT inhibition with Debio-025 is a novel treatment strategy in MD. Lastly, we tested whether calcium can cause a MD-like phenotype without a mutation in the DGC by transgenic overexpression of ion channels in skeletal muscle. Both sodium-calcium exchanger and transient receptor potential of the canonical class (TRPC3) transgenic animals display skeletal muscle disease suggesting calcium does contribute to the disease in MD. We have shown that inhibition of the calcium-sensitive MPT process reduces MD disease and increased intracellular calcium, independent of an unstable sarcolemma, results in disease similar to MD. Collectively, these results strongly suggest calcium is the central mediator of MD pathogenesis.
Jeffery Molkentin, PhD (Committee Chair)
146 p.
Molecular Biology
muscular dystrophy; calcium; mitochondrial permeability transition; cyclophilin D

Recommended Citations

Citations

  • Millay, D. P. (2008). Calcium as the central mediator of muscle dysfunction due to muscular dystrophy [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412

    APA Style (7th edition)

  • Millay, Douglas. Calcium as the central mediator of muscle dysfunction due to muscular dystrophy. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412.

    MLA Style (8th edition)

  • Millay, Douglas. "Calcium as the central mediator of muscle dysfunction due to muscular dystrophy." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211297412

    Chicago Manual of Style (17th edition)

ucin1211297412
873
© 2008, some rights reserved.Creative Commons License Calcium as the central mediator of muscle dysfunction due to muscular dystrophy by Douglas P. Millay is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.