5-Fluorouracil Alters Skeletal Muscle Mitochondrial Content And Inflammation In Mice

Abstract

5-fluorouracil (5FU) is one of the most widely used chemotherapy drugs for colon, breast, head & neck, and pancreatic cancers; however, 5FU’s non-selective cytotoxic effects lead to debilitating fatigue coupled with decrements in skeletal muscle health and function. PURPOSE: To investigate the impacts of 5FU on physical activity, indices of skeletal muscle function, and the underlying changes in skeletal muscle mitochondrial content and inflammation. METHODS: Adult male CD2F1 mice were subjected to 1 cycle of 5FU (cycle: 5d, 30 mg/kg Lean Mass, i.p.) or PBS control. Cage activity, grip strength and neuromuscular function were assessed and skeletal muscle protein was isolated 48 hours following the last dose of 5FU or PBS. Mitochondria biogenesis [transcription factor A (TFAM)] and total content [electron transport chain complexes I-V (CI-V), cytochrome c (CytoC), voltage-dependent anion channels (VDAC)] was analyzed via western blot analysis. Real-time polymerase chain reaction was performed to analyze skeletal muscle macrophage [CD68, EGF-like module-containing mucin-like hormone receptor-like 1 (EMR1), integrin subunit alpha X (Itgax), mannose receptor C-type 1 (MRC1)], pro-inflammatory [interleukin (IL) -1ß, -6, -13), tumor necrosis factor (TNF), interferon-gamma (IFNγ)] and anti-inflammatory [IL-10] gene expression. RESULTS: 5FU did not significantly impact grip strength or neuromuscular function (p > 0.05); however, cage activity and body weight (Δ8%) appreciably decreased following 5FU compared to controls (p < 0.05). Moreover, we observed a significant reduction in TFAM, VDAC, CIV, and CV following 5FU administration (p < 0.05) while no differences in CytoC, CI, CII, and CIII were found (p > 0.05). Interestingly, EMR1 (Δ43%) and CD68 (Δ37%) expression significantly decreased along with reductions in IL-1ß (Δ85%), IL-6 (Δ37%), TNF (Δ52%), and IFNγ (Δ42%) expression following 5FU compared to controls (p < 0.05). CONCLUSION: Collectively, these results demonstrate 1 cycle of 5FU notably impacts mitochondrial content and inflammation concomitant with decreases in body weight and cage activity. While changes in skeletal muscle function were not found, the observed changes in mitochondria and the inflammatory micro-environment may precede the functional decrements in skeletal muscle.