Doctor of Philosophy, The Ohio State University, 2013, Molecular, Cellular and Developmental Biology

Cachexia is a debilitating syndrome associated with multiple chronic diseases, including cancer. It is characterized by extreme weight loss primarily due to the depletion of skeletal muscle as well as adipose tissue. In cancer, patients that suffer from cachexia are more susceptible to dose-limiting toxicity in chemotherapy . Cachexia not only diminishes the quality of life of cancer patients, but is also positively related to cancer mortality. Pancreatic and other gastrointestinal cancers exhibit the highest incidence of cancer cachexia, with one third of these patients losing more than 10% of their pre-illness body weight. Efforts to understand the mechanism underlying cancer cachexia might eventually improve the treatment outcome as well as the quality of life of these and other cancer patients. Muscle wasting in cachexia results mainly from aberrant signaling of pathways that usually maintains a balance between protein synthesis and degradation. The increase in catabolism usually associates with a decrease in anabolism including the Akt and mTOR signaling pathways. Although events as such inside the myofibers have been firmly established to take place in cancer cachexia, relatively little is known about events outside the muscle fibers, in the muscle microenvironment, and their potential significance in regulating wasting in cancer cachexia. To understand whether events in the muscle microenvironment are dysregulated in cancer cachexia, we started out this study by examining the ultrathin sections of skeletal muscle using electron microscopy. We observed an abnormal accumulation of cells in the interstitial space of cachectic muscles from tumor bearing mice. We further identified these cells as activated muscle stem cells. Using cellular and genetic approaches in murine cachexia models and muscle biopsies from cachectic patients, we describe in detail cancer cachexia is associated with an impaired regeneration program, and this is due to compromised differentiat (open full item for complete abstract)

Committee: Denis Guttridge (Advisor); Kay Huebner (Committee Member); Paul Martin (Committee Member); Matthew Ringel (Committee Member) Subjects: Biology; Cellular Biology; Genetics; Molecular Biology

Doctor of Philosophy, Case Western Reserve University, 2009, Biochemistry

Ski is the most studied member of a family of proteins all sharing a conserved Dachshund homology domain. It has been implicated in oncogenic transformation, myogenic conversion of avian embryo fibroblasts and also many aspects of vertebrate development, especially myogenesis. Ski-/- mice exhibit severe defects in skeletal muscle and die at birth, yet little is know about either the underlying mechanisms or the role of Ski in adult muscle regeneration. In these studies, I used Ski knockout mice and C2C12 myoblast cultures to address these issues, respectively. Detailed analysis of Ski-/- embryos revealed dramatically reduced hypaxial muscles but less affected epaxial muscles. The reduced number of myogenic regulatory factor positive cells in Ski-/- mice suggested an insufficient myogenic cell pool to support muscle formation. However, both the dermomyotomal hypaxial progenitors and myotomal epaxial progenitors formed and committed to myogenic fate appropriately. The hypaxial muscle defect in Ski-/- mice was not caused by abnormal proliferation, terminal differentiation or apoptosis of the myogenic cells either, but due to impaired migration of embryonic hypaxial progenitors. Surprisingly, the normal distribution of fetal/postnatal myogenic progenitors in Ski-/- mice suggested different effects of Ski on the behaviors of embryonic and fetal/postnatal myogenic progenitors. In addition, although not affecting the terminal differentiation of embryonic myogenic cells, Ski was necessary for that of adult satellite-cell derived C2C12 myoblasts as evidenced by impaired myotube formation and reduced induction of genes essential for myogenic differentiation in the absence of Ski. This function was mainly mediated by Ski's ability to form a complex with Six1 and Eya3 and activate Myog transcription through a MEF3 site. It is important in the future to further study mechanisms underlying the contrasting effects of Ski on embryonic, fetal and adult muscle development, to investi (open full item for complete abstract)

Committee: David Samols PhD (Committee Chair); Ed Stavnezer PhD (Advisor); Clemencia Colmenares PhD (Committee Member); Nikki Harter PhD (Committee Member); Lynn Landmesser PhD (Committee Member) Subjects: Biomedical Research