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Regulation of Branched‐Chain Alpha‐Keto Acid Dehydrogenase During Muscle Cell Differentiation
Author(s) -
Beatty Brendan,
Dhanani Zameer,
Adegoke Olasunkanmi John
Publication year - 2017
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.31.1_supplement.lb465
Subject(s) - catabolism , skeletal muscle , myocyte , endocrinology , downregulation and upregulation , biology , medicine , leucine , branched chain amino acid , anabolism , protein turnover , valine , biochemistry , chemistry , amino acid , metabolism , protein biosynthesis , gene
Skeletal muscles are critical to locomotion and whole‐body substrate metabolism; their mass and function also affect quality of life. Suboptimal muscle mass and function underlie or worsen chronic catabolic conditions like uncontrolled diabetes and several cancers. They are also predictive of treatment outcomes and survival. As a result, studies into mechanisms of muscle preservation and regeneration hold potential to improve patient outcomes. Muscle mass is a function of muscle cell number and protein balance. While muscle protein balance can be regulated by nutrition, especially the branched‐chain amino acids (BCAA: leucine, isoleucine and valine), the effect of nutrition on muscle cell formation and regeneration has received little attention. In addition, recent metabolomics studies have implicated metabolites of BCAA in both the activation of anabolic signaling and in prognosis of chronic disease, but little is known about the effects of these metabolites and the pathway that generate them on muscle cell formation. The first irreversible and rate limiting reaction involved in BCAA catabolism is regulated by an enzyme complex, branched‐chain alpha‐keto acid dehydrogenase (BCKD). Working with rodent muscle cells, we showed that the abundance of BCKDE1a subunit was upregulated during cell differentiation (up to 5X, P<0.05) without a corresponding change in mRNA level. BCKD activity is antagonistically regulated by a phosphatase (positively), and a kinase (negatively). BCKD kinase abundance tended to rise during differentiation along with a decrease in BCKD activity. Myoblasts depleted of BCKDE1a had impaired myotube formation and marked reduction in the expression of myofibrillar proteins. Collectively, these data highlight the significance of BCAA catabolism during cell differentiation and suggest that interventions that target BCKD abundance hold promise for muscle regeneration. Support or Funding Information NSERC, Faculty of Health at York University