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Dissertation/Thesis Abstract

The Role of Adenosine Monophosphate Deaminase 1 (AMPD1) and Inflammatory Cytokines in Mediating Muscle Weakness in a Mouse Model of Idiopathic Inflammatory Myopathy
by Coley, William, Ph.D., The George Washington University, 2013, 117; 3544264
Abstract (Summary)

PROBLEM: Myositis is a term used to describe a group of related autoimmune diseases that affect skeletal muscle tissues. These diseases are also described as idiopathic inflammatory myopathies, reflecting that they are characterized by significant muscle weakness and lymphocyte infiltration into the muscle tissue due to unknown causes. Patients with myositis will typically be diagnosed with one of the three most common varieties: polymyositis, dermatomyositis, or inclusion body myositis. While there is no question that there is an autoimmune reaction in these patients, it has been observed that there is dissociation between autoimmune inflammation and muscle weakness. Treatment with immunosuppressive compounds does not guarantee a recovery in muscle function, and there is a poor correlation between degree of infiltration and muscle weakness. In essence, there is a non-immune component that may cause muscle weakness in this disease.

OBJECTIVE: Prior investigations in humans have suggested a potential mechanism that is independent of the action of autoreactive T-lymphocytes or autoantibodies to explain muscle weakness in patients. It has been proposed that the persistent weakness is due to an acquired deficiency of the metabolic enzyme adenosine monophosphate deaminase (AMPD1). While there is substantial data to support this hypothesis, it cannot be directly tested in humans. We were able test this hypothesis in an inducible transgenic mouse model of myositis that closely mimics the human disease phenotype. Using these mice, we tested the proposed hypothesis that a) AMPD1 is responsible for muscle weakness in myositis, b) supplements of D-ribose can replace the downstream metabolites of AMPD1 and ameliorate disease symptoms and c) cytokines of the innate immune response modulate the expression of AMPD1. This work required in vitro skeletal muscle cell culture techniques and in vivo mouse phenotyping, histological, molecular, genetic and biochemical assays.

RESULTS: We observed that the onset of muscle weakness does indeed coincide with an acquired deficiency of AMPD1 in skeletal muscle, in addition to a general suppression of enzymes related to glycolysis. The loss of AMPD1 was specific to myositis, and not observed in other myopathies. We made the novel observation that muscle weakness and decreased AMPD1 activity occurred prior to the appearance of infiltrating lymphocytes in skeletal muscle tissue. We found that the partial knockdown of AMPD1 in mice resulted in significant muscle weakness in healthy mice, and corroborated this data with mice heterozygous for the AMPD1 gene. We observed that metabolites downstream of AMPD1 (e.g. IMP and hypoxanthine) were significantly decreased. Attempts to replace these metabolites with oral supplements of D-ribose proved to be ineffective as a treatment. We found that innate immune cytokines such as Type I interferons and Interleukin-1b were able to inhibit the expression of AMPD1 in vitro and induce weakness in vivo. Additionally, we observed that IL-15 had a stimulatory effect on the expression of AMPD1 and that mice with myositis had significantly lower levels of the IL-15 receptor. These data for the first time demonstrate a link between innate immune systems and energy generating muscle metabolic pathways. Future experiments to modulate this link between innate immune system and metabolic pathway would identify newer drugs that specifically target muscle weakness and thus improve the quality of life for patients with myositis.

Indexing (document details)
Advisor: Nagaraju, Kanneboyina
Commitee: Andrade, Philipe, Chen, Yi-Wen, Devaney, Joseph, Freishtat, Robert, Radoja, Sasa, Rose, Mary C.
School: The George Washington University
Department: Biomedical Sciences
School Location: United States -- District of Columbia
Source: DAI-B 74/03(E), Dissertation Abstracts International
Subjects: Molecular biology, Microbiology, Immunology
Keywords: Ampd1, Autoimmune, Idiopathic inflammatory myopathy, Inflammation, Muscle weakness, Myositis
Publication Number: 3544264
ISBN: 978-1-267-74312-1
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