Abstract
In cancer patients, chemotherapeutic medication induces aberrant ROS (reactive oxygen species) accumulation in skeletal muscles, resulting in myofiber degradation, muscle weakness, and even cachexia, which further leads to poor therapeutic outcomes. Acting as an antioxidant, taurine is extensively used to accelerate postexercise muscle recovery in athletes. The antioxidant effects of taurine have been shown in mature myotubes and myofibers but not yet in myoblasts, the myotube precursor. The proliferation and differentiation ability of myoblasts play a very important role in myofiber repair and regeneration, which is usually impaired during chemotherapeutics in cancer patients as well. Here, we explored the effects of taurine supplementation on C2C12 myoblasts exposed to cisplatin-induced ROS. We found that cisplatin treatment led to dramatically decreased cell viability; accumulated ROS level; down-regulated expressions of MyoD1 (myoblast determination protein 1), myogenin, and MHC (myosin heavy chain); and impaired myotube differentiation in myoblasts. Significantly, taurine supplementation protected myoblasts against cisplatin-induced cell viability decrease, promoted cellular ROS clearance, and, most importantly, preserved the expressions of MyoD1, myogenin, and MHC as well as myotube differentiation ability. We further conducted NMR-based metabolomic analysis to clarify the underlying molecular mechanisms. We identified 14 characteristic metabolites primarily responsible for the discrimination of metabolic profiles between cisplatin-treated cells and normal counterparts, including increased levels of BCAAs (branched-chain amino acids: leucine and isoleucine), alanine, glycine, threonine, glucose, ADP (adenosine diphosphate), phenylalanine, and PC (O-phosphocholine), and decreased levels of lysine, β-alanine, choline, GPC (sn-glycero-3-phosphocholine), and myo-inositol. Evidently, taurine supplementation partially reversed the changing trends of several metabolites (isoleucine, threonine, glycine, PC, β-alanine, lysine, and myo-inositol). Furthermore, taurine supplementation promoted the proliferation and myotube differentiation of myoblasts by alleviating cellular catabolism, facilitating GSH (reduced glutathione) biosynthesis, improving glucose utilization and TCA (tricarboxylic acid) cycle anaplerosis, and stabilizing cellular membranes. Our results demonstrated the protective effects of taurine on cisplatin-impaired myoblasts and elucidated the mechanistic rationale for the use of taurine to ameliorate muscle toxicity in clinical chemotherapy cancer patients.
Highlights
Skeletal muscle is physiologically essential for human somatic functions such as movement, posture maintenance, heat generation, and breathing (Frontera and Ochala, 2015), which are all energy consuming
Given that myoblasts play a critical role in the post-damage regeneration of myofibers, we investigated in this study the effects of taurine supplementation on murine C2C12 myoblasts impaired by cisplatin treatment
We have demonstrated that taurine supplementation protected C2C12 myoblasts against cell viability decrease, facilitated intracellular reactive oxygen species (ROS) clearance, and, most importantly, partially preserved the myotube differentiation ability of cisplatinimpaired myoblasts
Summary
Skeletal muscle is physiologically essential for human somatic functions such as movement, posture maintenance, heat generation, and breathing (Frontera and Ochala, 2015), which are all energy consuming. Mitochondria possess a central role in energy production through oxidative phosphorylation. The inherent motion attribute of skeletal muscles is usually accompanied by the production of oxidative stress, which potentially results in myofiber damage upon untimely clearance (Steinbacher and Eckl, 2015; Magherini et al, 2019; Cheng et al, 2020). Some antineoplastic drugs exhibit high tendencies of muscle toxicity by inducing ROS production (Kodera, 2015; Chen et al, 2016; Kakinuma et al, 2018; Matsuura et al, 2020). Longterm cisplatin medication can induce aberrant ROS accumulation in skeletal muscle cells and lead to systemic muscle impairments including promoted muscle catabolism, apoptosis, and autophagy, and cumulated poor therapeutic response and outcome in cancer patients (Sakai et al, 2014; Conte et al, 2020). Few efficient approaches have been developed for the treatment of cancer patients through directly ameliorating muscle toxicities during chemotherapy
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