Abstract
Skeletal muscle (SM) health and integrity is dependent on the dynamic balance between protein synthesis and degradation, and central to this process is the availability of amino acids (AA) in the amino pool. While Doxorubicin (DOX) remains one of the most widely used chemotherapeutic agents for the treatment of solid and hematological malignancies, little is known of the effect of the drug on SM, particularly its effect on the availability of amino acids in the tissue. The purpose of this study was to examine the effect of DOX administration on vascular, interstitial and intracellular concentrations of AA in SM of the rat up to 8 days after the administration of a 1.5 or 4.5 mg/kg i.p. dose of DOX. In the plasma, total amino acids (TAA) were significantly increased compared to control where greater (P<0.05) concentrations were observed following the 1.5 mg/kg dose compared to the 4.5 mg/kg dose. Compared to control, the 1.5 mg/kg dose resulted in an increase (P<0.05) in interstitial TAA whereas the 4.5 mg/kg resulted in a sustained decrease (P<0.05). Intracellular TAA, essential amino acids (EAA) and branched-chain amino acids (BCAA) where significantly increased in each muscle group analyzed, following the 1.5 and 4.5 mg/kg doses compared to control. This study provides important insight into the amino acid response following DOX chemotherapy and presents a substantial foundation for future studies focused on reducing SM damage and recovery by targeting amino acid metabolism.
Highlights
Skeletal muscle represents the largest organ in the human body, composing ~40% of the total body weight and in addition to its mechanical function, skeletal muscle plays a key role in whole body metabolism [1, 2]
Muscle mass is dependent on the dynamic balance between protein synthesis and degradation, and central to this process is the availability of amino acids in the free amino acid pool
Since the direction of all the individual amino acids following the administration of DOX are similar, changes in the amino acid pool will be descrbied via changes in total amino acids. essential amino acids and branched-chain amino acids
Summary
Skeletal muscle represents the largest organ in the human body, composing ~40% of the total body weight and in addition to its mechanical function, skeletal muscle plays a key role in whole body metabolism [1, 2]. Muscle mass is dependent on the dynamic balance between protein synthesis and degradation, and central to this process is the availability of amino acids in the free amino acid pool. Approximately 130 gms of free amino acids are present in the skeletal muscle intracellular space [3] and, in addition to its role in muscle protein turnover, amino acids participate in numerous metabolic reactions that take place in tissues throughout the body. Skeletal muscle amino acid pool following doxorubicin chemotherapy and degradation where net protein breakdown is greater than that of synthesis in skeletal muscle can result in a cachectic, or muscle wasting, condition. The use of anti-cancer chemotherapeutics such as that of Doxorubicin may play a role in the onset of cachexia in cancer patients undergoing chemotherapy
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