(OR02-01-24) Narirutin Ameliorates Cisplatin-Induced Muscle Atrophy by Regulating Protein Degradation and Synthesis With Mitochondrial Function In Vitro and In Vivo

Objectives: Cisplatin is the first-line chemotherapeutic agent for treating non-small cell lung cancer, which is the leading cause of cancer death. However, cisplatin-induced mitochondrial dysfunction leads to muscle atrophy, resulting in treatment discontinuation or poor quality of life in cancer patients. Considering narirutin (NR), a flavanone, has anti-oxidant and anti-inflammatory properties, we investigated the effects of narirutin on cisplatin-induced muscle atrophy and mitochondrial function.

Methods: C2C12 myotubes differentiated in the presence of NR (0‐10 µM) and cisplatin (30 µM) were analyzed for MHC immunostaining, MitoTracker, and JC-1 assay. Male C57BL/6 mice were assigned to normal control, tumor control, tumor+cisplatin (4 mg/kg), tumor+cisplatin+NR 10 mg/kg, or tumor+cisplatin+NR 20 mg/kg groups. Grip strength and wire hanging tests were performed to evaluate muscle strength. Quadriceps muscle tissues were analyzed for muscle fiber cross-sectional area and expression of markers related with myogenesis, protein synthesis and degradation, and mitochondrial function.

Results: NR improved myogenic differentiation, mitochondrial mass, and mitochondrial membrane potential in C2C12 myotubes treated with cisplatin. Similarly, NR supplementation improved average food intake, muscle strength, muscle weight, and cross-sectional area in vivo. NR supplementation decreased the expression of muscle atrophy markers such as MuRF1 and MAFbx by suppressing IL-6/STAT3, TNFα/NF-κB, and p38MAPK signaling pathways. Conversely, it upregulated the expression of myogenic markers including MyHC ⅡA, MyHC ⅡX, and MyHC Ⅰ via activation of IGF-1R/PI3K/Akt/mTOR pathway. Of note, NR significantly upregulated the expression of markers related with mitochondrial biogenesis and fusion (AMPK, PGC1α, NRF, TFAM, OPA1, and MFN2), which was in accordance with the enhanced expression of Parkin and Beclin-1 that mediates mitophagy.

Conclusions: NR ameliorates cisplatin-induced muscle atrophy by regulating imbalance between protein degradation and synthesis pathways in association with the improvement of mitochondrial dysfunction. Our findings indicate NR has a potential as a nutritional supplement for the prevention and treatment of muscle atrophy in cancer patients receiving cisplatin.

Funding Sources: National Research Foundation of Korea