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osu1180096565.pdf (5.7 MB)
ETD Abstract Container
Abstract Header
Elucidating molecular mechanisms of muscle wasting in chronic diseases
Author Info
Acharyya, Swarnali
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1180096565
Abstract Details
Year and Degree
2007, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science.
Abstract
Skeletal muscle represents one of the most abundant tissues in our body that primarily acts as a protein reservoir and maintains the structural framework. Skeletal muscle maintains its mass and functionality by balancing the rate of muscle synthesis and degradation. Disruption of this intricate balance results in debilitating wasting conditions such as myopathies and dystrophies that not only adversely affects skeletal muscle but also promotes whole body catabolism. My research has been focused on understanding the molecular mechanisms that regulate skeletal muscle wasting in chronic disease states. In cancer mediated muscle wasting, we utilized a morphological approach to characterize structural changes in a cachectic muscle. Using murine models of cancer cachexia as well as clinical samples from cancer patients, these studies have elucidated three main molecular changes in a cachectic muscle. One of the early visible alterations involved membrane abnormalities, accompanied by the loss and post-translational modifications in the members of a multimeric protein complex known as the dystrophin glycoprotein complex (DGC), mostly implicated in muscular dystrophies. Contrary to the commonly accepted notion, the third event in muscle wasting was a highly selective and tightly controlled process. Among the myriad of proteins that comprise skeletal muscle, the core myofibrillar protein, myosin heavy chain was found to be a preferred target of the degradation machinery in cancer cachexia. Primarily deregulated in response to tumor factors in cancer, DGC function is instead inactivated by mutations in muscular dystrophies. DGC alterations thus served as a commonality between the two myopathies that propelled us to further investigate the molecular mechanisms in muscular dystrophies. A signaling network that is highly activated in muscular dystrophiesis the IKK/NF-kB signaling pathway. To elucidate the role of this signaling pathway in Duchenne muscular dystrophy (DMD), we have utilized conditional mutants as well as pharmacological inhibitors of the IKK signaling pathway in mdx mice, a mouse model of DMD. Our results indicate that NF-kB signaling in activated macrophages functions to promote inflammation and muscle necrosis and in skeletal muscle fibers limits the regenerative capacity through the inhibition of muscle progenitor cells.
Committee
Denis Guttridge (Advisor)
Pages
184 p.
Subject Headings
Biology, Genetics
Keywords
skeletal muscle
;
dystrophin
;
regeneration
;
dystrophin
;
cachexia
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Citations
Acharyya, S. (2007).
Elucidating molecular mechanisms of muscle wasting in chronic diseases
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1180096565
APA Style (7th edition)
Acharyya, Swarnali.
Elucidating molecular mechanisms of muscle wasting in chronic diseases.
2007. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1180096565.
MLA Style (8th edition)
Acharyya, Swarnali. "Elucidating molecular mechanisms of muscle wasting in chronic diseases." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1180096565
Chicago Manual of Style (17th edition)
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Document number:
osu1180096565
Download Count:
960
Copyright Info
© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.