Basic Science| Volume 123, 154864, October 2021

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AMP deamination is sufficient to replicate an atrophy-like metabolic phenotype in skeletal muscle

  • Spencer G. Miller
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Kinesiology, East Carolina University, Greenville, NC, USA
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  • Paul S. Hafen
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Andrew S. Law
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Catherine B. Springer
    Department of Kinesiology, East Carolina University, Greenville, NC, USA
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  • David L. Logsdon
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Thomas M. O'Connell
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Carol A. Witczak
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Jeffrey J. Brault
    Corresponding author at: Dept. of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5035, Indianapolis, IN 46202, USA.
    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
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      • AMP deaminase (AMPD) decreases ATP without activating AMPK or its substrates.
      • AMPD alters the intracellular metabolome similar to atrophic muscle.
      • AMPD slows mitochondria synthesis and oxygen consumption similar to atrophic muscle.
      • Metabolome shift is independent of metabolic genes and precede mitochondria changes.



      Skeletal muscle atrophy, whether caused by chronic disease, acute critical illness, disuse or aging, is characterized by tissue-specific decrease in oxidative capacity and broad alterations in metabolism that contribute to functional decline. However, the underlying mechanisms responsible for these metabolic changes are largely unknown. One of the most highly upregulated genes in atrophic muscle is AMP deaminase 3 (AMPD3: AMP → IMP + NH3), which controls the content of intracellular adenine nucleotides (AdN; ATP + ADP + AMP). Given the central role of AdN in signaling mitochondrial gene expression and directly regulating metabolism, we hypothesized that overexpressing AMPD3 in muscle cells would be sufficient to alter their metabolic phenotype similar to that of atrophic muscle.


      AMPD3 and GFP (control) were overexpressed in mouse tibialis anterior (TA) muscles via plasmid electroporation and in C2C12 myotubes using adenovirus vectors. TA muscles were excised one week later, and AdN were quantified by UPLC. In myotubes, targeted measures of AdN, AMPK/PGC-1α/mitochondrial protein synthesis rates, unbiased metabolomics, and transcriptomics by RNA sequencing were measured after 24 h of AMPD3 overexpression. Media metabolites were measured as an indicator of net metabolic flux. At 48 h, the AMPK/PGC-1α/mitochondrial protein synthesis rates, and myotube respiratory function/capacity were measured.


      TA muscles overexpressing AMPD3 had significantly less ATP than contralateral controls (−25%). In myotubes, increasing AMPD3 expression for 24 h was sufficient to significantly decrease ATP concentrations (−16%), increase IMP, and increase efflux of IMP catabolites into the culture media, without decreasing the ATP/ADP or ATP/AMP ratios. When myotubes were treated with dinitrophenol (mitochondrial uncoupler), AMPD3 overexpression blunted decreases in ATP/ADP and ATP/AMP ratios but exacerbated AdN degradation. As such, pAMPK/AMPK, pACC/ACC, and phosphorylation of AMPK substrates, were unchanged by AMPD3 at this timepoint. AMPD3 significantly altered 191 out of 639 detected intracellular metabolites, but only 30 transcripts, none of which encoded metabolic enzymes. The most altered metabolites were those within purine nucleotide, BCAA, glycolysis, and ceramide metabolic pathways. After 48 h, AMPD3 overexpression significantly reduced pAMPK/AMPK (−24%), phosphorylation of AMPK substrates (−14%), and PGC-1α protein (−22%). Moreover, AMPD3 significantly reduced myotube mitochondrial protein synthesis rates (−55%), basal ATP synthase-dependent (−13%), and maximal uncoupled oxygen consumption (−15%).


      Increased expression of AMPD3 significantly decreased mitochondrial protein synthesis rates and broadly altered cellular metabolites in a manner similar to that of atrophic muscle. Importantly, the changes in metabolites occurred prior to reductions in AMPK signaling, gene expression, and mitochondrial protein synthesis, suggesting metabolism is not dependent on reductions in oxidative capacity, but may be consequence of increased AMP deamination. Therefore, AMP deamination in skeletal muscle may be a mechanism that alters the metabolic phenotype of skeletal muscle during atrophy and could be a target to improve muscle function during muscle wasting.


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