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AMP Deaminase 3 Accelerates Protein Degradation in C2C12 Myotubes
Author(s) -
Davis Patrick,
Witczak Carol,
Brault Jeffrey
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.825.2
Subject(s) - myogenesis , muscle atrophy , protein degradation , atrophy , proteolysis , medicine , skeletal muscle , protein turnover , endocrinology , chemistry , myocyte , anabolism , sarcopenia , c2c12 , biochemistry , biology , protein biosynthesis , enzyme
Skeletal muscle atrophy is characterized by increased rates of protein degradation and net loss of protein. Unfortunately, there are no suitable pharmaceutical treatments for atrophy. The expression of AMP Deaminase 3 (AMPD3: AMP ↔ IMP + NH 3 ), which degrades high‐energy adenine nucleotides, is increased up to 100‐fold during atrophy, but surprisingly its function in atrophy is unknown. The purpose of this study was to determine if increased AMPD3 expression alone would accelerate protein degradation and thus initiate muscle atrophy. Methods C2C12 myotubes were infected with adenoviruses encoding AMPD3 or GFP. Protein degradation and protein synthesis rates were determined by the pulse‐chase of 3 H‐tyrosine. Total AMPD activity (IMP formation) and nucleotide (ATP, ADP, AMP, and IMP) content were measured in cell homogenates by UPLC. Results AMPD3 overexpression for 24 h significantly increased AMPD activity and [IMP], demonstrating a sustained mismatch between energy supply and demand. Degradation rate of long‐lived proteins was greater in AMPD3 (1.17%/hr) vs GFP controls (0.85%/hr) (p<0.01), while protein synthesis rate remained unchanged. The accelerated proteolysis rate was entirely sufficient to explain the 15% lower (p<0.01) total protein content in AMPD3 infected myotubes. Conclusions These data demonstrate that AMPD3 overexpression in muscle creates an energetic imbalance and initiates atrophy through increased proteolysis. Therefore, our data implicate AMPD3 and perhaps cellular energetics as promising targets for new treatments of atrophy. ACSM Foundation Grant.