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Metabolism of the Branched‐Chain Amino Acids are Disrupted by Chemotherapy Drugs
Author(s) -
Mora Stephen,
Adegoke Olasunkanmi
Publication year - 2021
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.2021.35.s1.02035
Subject(s) - myogenesis , cachexia , myosin , chemistry , medicine , biochemistry , endocrinology , skeletal muscle , pharmacology , biology , cancer
Cachexia is a devastating muscle‐wasting condition found in many diseases, including cancer, chronic kidney disease and heart failure. Aside from both tumour burden and disease‐related malnutrition, the development of cachexia is associated with chemotherapy treatment. Branched‐ chain amino acids (BCAA: leucine, isoleucine and valine) are critical regulators of skeletal muscle protein anabolism due to their activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). However, BCAA supplementation/nutritional support does not fully reverse chemotherapy‐induced cachexia. Therefore, we investigated whether breakdown of BCAAs is affected by chemotherapy drugs. On day 4 of differentiation, L6 myotubes were treated with vehicle (1.4μL/mL DMSO) or a common chemotherapy drug cocktail, folfiri (a mixture of CPT‐11 (20μg/mL), leucovorin (10μg/mL), and 5‐fluorouracil (50μg/mL)) for 24‐48h. Myotubes treated with folfiri exhibited ~30% reductions in myotube diameter (p < 0.05, n=3) and ~50% reductions in abundance of myofibrillar proteins myosin heavy chain‐1 (MHC) and troponin (p < 0.05). Protein content of branched‐chain alpha‐ketoacid dehydrogenase complex (BCKD), the enzyme responsible for the irreversible decarboxylation of the BCAA ketoacids, was unchanged following folfiri treatment. However, the activity of this enzyme complex was significantly decreased (~20%) 24 and 48h following treatment with folfiri (p < 0.05). Branched‐chain alpha‐ketoacid dehydrogenase complex kinase (BDK), a negative regulator of BCKD, was increased 24h (~20%), but unchanged at 48h following folfiri treatment. Compared to vehicle, folfiri‐treated myotubes showed a non‐significant reduction (~30%) in phenylalanine incorporation into proteins. In line with studies showing a link between impaired BCAA catabolism and insulin resistance, our data suggest a link between chemotherapy‐induced muscle atrophy and altered BCAA catabolism.