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      Cessation of biomechanical stretch model of C2C12 cells models myocyte atrophy and anaplerotic changes in metabolism using non-targeted metabolomics analysis

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          Abstract

          Studies of skeletal muscle disuse, either in patients on bed rest or experimentally in animals (immobilization), have demonstrated that decreased protein synthesis is common, with transient parallel increases in protein degradation. Muscle disuse atrophy involves a process of transition from slow to fast myosin fiber types. A shift toward glycolysis, decreased capacity for fat oxidation, and substrate accumulation in atrophied muscles have been reported, as has accommodation of the liver with an increased gluconeogenic capacity. Recent studies have modeled skeletal muscle disuse by using cyclic stretch of differentiated myotubes (C2C12), which mimics the loading pattern of mature skeletal muscle, followed by cessation of stretch. We utilized this model to determine the metabolic changes using non-targeted metabolomics analysis of the media. We identified increases in amino acids resulting from muscle atrophy-induced protein degradation (largely sarcomere) that occurs with muscle atrophy that are involved in feeding the Kreb's cycle through anaplerosis. Specifically, we identified increased alanine/proline metabolism (significantly elevated proline, alanine, glutamine, and asparagine) and increased α-ketoglutaric acid, the proposed Kreb's cycle intermediate being fed by the alanine/proline metabolic anaplerotic mechanism. Additionally, several unique pathways not clearly delineated in previous studies of muscle unloading were seen, including: (1) elevated keto-acids derived from branched chain amino acids (i.e. 2-ketoleucine and 2-keovaline), which feed into a metabolic pathway supplying acetyl-CoA and 2-hydroxybutyrate (also significantly increased); and (2) elevated guanine, an intermediate of purine metabolism, was seen at 12h unloading. Given the interest in targeting different aspects of the ubiquitin proteasome system to inhibit protein degradation, this C2C12 system may allow the identification of direct and indirect alterations in metabolism due to anaplerosis or through other yet to be identified mechanisms using a non-targeted metabolomics approach.

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          Author and article information

          Journal
          The International Journal of Biochemistry & Cell Biology
          The International Journal of Biochemistry & Cell Biology
          Elsevier BV
          13572725
          October 2016
          October 2016
          : 79
          : 80-92
          Article
          10.1016/j.biocel.2016.08.012
          5067204
          27515590
          7a029a3a-b6ae-47f2-97f4-62d8f446b83d
          © 2016

          https://www.elsevier.com/tdm/userlicense/1.0/

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