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Myotube Morphology and Protein Metabolism are Negatively Regulated by Chemotherapy Drugs
Author(s) -
Mora Stephen,
Adegoke Olasunkanmi John
Publication year - 2019
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.2019.33.1_supplement.700.19
Subject(s) - mtorc1 , myogenesis , ribosomal protein s6 , cachexia , myofibril , myosin , p70 s6 kinase 1 , pharmacology , chemotherapy , endocrinology , medicine , biology , chemistry , cancer research , phosphorylation , protein kinase b , cancer , myocyte , microbiology and biotechnology
Cachexia, a condition prevalent in many cancer patients, is characterized by weight loss and fatigue resulting from decreases in muscle mass and function. Severity of cachexia negatively correlates with treatment outcomes, drug toxicity and survival. Tumor burden and cancer related‐malnutrition have been implicated in the development of the condition. Other studies have suggested a causative link between chemotherapy treatment and cachexia. To understand the mechanisms of effects of these drugs on cachexia, we investigated the effects of a common chemotherapy drug cocktail on myotube morphology, myofibrillar protein abundance, and mTORC1 signalling. On day 4 of differentiation, myotubes were treated with vehicle or a chemotherapy drug cocktail (a mixture of cisplatin (20 μg/mL), leucovorin (10 μg/mL), and 5 fluorouracil (50 μg/mL)). Compared to myotubes treated with vehicle, those treated with the drug cocktail showed dysmorphic shape and shrinkage. Drug treatment also induced a 50% decrease in the abundance of myosin heavy chain (n = 5 independent experiments, P = 0.0001), 80% reduction in troponin and tropomyosin (n=3–4, P < 0.0003) by day 6 of differentiation. To explore the reasons for the low abundance of these myofibrillar proteins, we examined treatment effects on mTORC1 (mammalian/mechanistic target of rapamycin complex 1), a signaling complex whose activity is vital for muscle anabolism. Myotubes treated with the drug cocktail showed 75% reduction in the phosphorylation of mTORC1 activator AKT (n = 3, P = 0.0061), and ≥70% reduction in phosphorylation status of mTORC1 substrates ribosomal protein S6 and its kinase, S6K1 (n = 3, P < 0.03). Drug treatment also led to 50–75% decreases in markers of mitochondria content cytochrome C oxidase (COX IV) and pyruvate dehydrogenase (P < 0.05). Because of the link between AKT activation and regulation of both protein synthesis and proteolysis, these data suggest that chemotherapy drugs decrease the abundance of myofibrillar proteins likely through the modulation of pathways that regulate protein synthesis and degradation, and mitochondrial content. To improve treatment outcomes and quality of life of patients, it is critical to identify interventions that can limit the negative effects of these drugs on muscle protein status and mitochondrial content. Support or Funding Information Natural Science and Engineering Research Council of Canada This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .