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    AMP Deaminase 3 in Skeletal Muscle Atrophy: Regulation of Protein Degradation and Contractile Performance

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    Author
    Davis, Patrick R.
    Abstract
    Skeletal muscle atrophy is characterized by depressed cellular energetics, increased rates of protein degradation, contractile deficits and loss of muscle mass. A potential regulator of these impairments is the metabolic enzyme AMP Deaminase 3, which is highly upregulated during most if not all types of atrophy. The goals of the present dissertation were: 1) to investigate the role of AMPD3 on energetics and contractile characteristics of skeletal muscle during atrophy and 2) to determine the effects of AMPD3 in muscle cells on adenine nucleotide content and protein degradation. AMPD3 was knocked down by electroporation of shRNA plasmids into mouse soleus muscle during denervation-induced atrophy. One week later, muscles were removed, electrically stimulated, and contractile function measured. Muscle homogenates were analyzed by UPLC and western blot. Denervation increased AMPD3 protein expression by 67%, while knockdown reduced AMPD3 by 60%. Knockdown of AMPD3 increased half relaxation times in both innervated and denervated muscles during tetanic and high intensity fatiguing contractions. Neither low intensity contractions nor overexpression of AMPD3 in non-atrophying muscles altered half relaxation time. To determine the effects of AMPD3 on protein degradation, AMPD3 was overexpressed by adenovirus in C2C12 myotubes. Adenine nucleotides, protein degradation rate, and indices of the major protein degradative pathways were measured. Overexpression of AMPD3 resulted in a 40% loss of ATP and an increase in IMP. Protein degradation rate was 38% greater while protein synthesis was unchanged, which resulted in a net loss of protein and myotube atrophy. Surprisingly, the autophagy activator ULK1 and apparent autophagic flux were unchanged. Further, proteasome subunit contents and in-vitro proteasome activity were similarly unchanged. However, consistent with greater protein degradation, total ubiquitinated conjugates decreased. The increase in half relaxation time with AMPD3 knockdown is consistent with the role of AMPD in preserving the free energy of ATP hydrolysis and SERCA function. Overexpression of AMPD3 also resulted in a loss of adenine nucleotides and acceleration of protein degradation, suggesting that a fall in ATP activates proteasomal degradation in-vivo. These exciting findings identify AMPD3 as a novel regulator of skeletal muscle performance and protein degradation during atrophy.
    URI
    http://hdl.handle.net/10342/5118
    Subject
     AMP deaminase; Protein degradation; Energetics 
    Date
    2015-11-23
    Citation:
    APA:
    Davis, Patrick R.. (November 2015). AMP Deaminase 3 in Skeletal Muscle Atrophy: Regulation of Protein Degradation and Contractile Performance (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/5118.)

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    MLA:
    Davis, Patrick R.. AMP Deaminase 3 in Skeletal Muscle Atrophy: Regulation of Protein Degradation and Contractile Performance. Doctoral Dissertation. East Carolina University, November 2015. The Scholarship. http://hdl.handle.net/10342/5118. August 17, 2022.
    Chicago:
    Davis, Patrick R., “AMP Deaminase 3 in Skeletal Muscle Atrophy: Regulation of Protein Degradation and Contractile Performance” (Doctoral Dissertation., East Carolina University, November 2015).
    AMA:
    Davis, Patrick R.. AMP Deaminase 3 in Skeletal Muscle Atrophy: Regulation of Protein Degradation and Contractile Performance [Doctoral Dissertation]. Greenville, NC: East Carolina University; November 2015.
    Collections
    • Dissertations
    • Kinesiology
    Publisher
    East Carolina University

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