Research Article: Cyclophosphamide leads to persistent deficits in physical performance and in vivo mitochondria function in a mouse model of chemotherapy late effects

Date Published: July 10, 2017

Publisher: Public Library of Science

Author(s): Marie-Laure Crouch, Gary Knowels, Rudolph Stuppard, Nolan G. Ericson, Jason H. Bielas, David J. Marcinek, Karen L. Syrjala, Dhyan Chandra.

http://doi.org/10.1371/journal.pone.0181086

Abstract

Fatigue is the symptom most commonly reported by long-term cancer survivors and is increasingly recognized as related to skeletal muscle dysfunction. Traditional chemotherapeutic agents can cause acute toxicities including cardiac and skeletal myopathies. To investigate the mechanism by which chemotherapy may lead to persistent skeletal muscle dysfunction, mature adult mice were injected with a single cyclophosphamide dose and evaluated for 6 weeks. We found that exposed mice developed a persistent decrease in treadmill running time compared to baseline (25.7±10.6 vs. 49.0±16.8 min, P = 0.0012). Further, 6 weeks after drug exposure, in vivo parameters of mitochondrial function remained below baseline including maximum ATP production (482.1 ± 48.6 vs. 696.2 ± 76.6, P = 0.029) and phosphocreatine to ATP ratio (3.243 ± 0.1 vs. 3.878 ± 0.1, P = 0.004). Immunoblotting of homogenized muscles from treated animals demonstrated a transient increase in HNE adducts 1 week after exposure that resolved by 6 weeks. However, there was no evidence of an oxidative stress response as measured by quantitation of SOD1, SOD2, and catalase protein levels. Examination of mtDNA demonstrated that the mutation frequency remained comparable between control and treated groups. Interestingly, there was evidence of a transient increase in NF-ĸB p65 protein 1 day after drug exposure as compared to saline controls (0.091±0.017 vs. 0.053±0.022, P = 0.033). These data suggest that continued impairment in muscle and mitochondria function in cyclophosphamide-treated animals is not linked to persistent oxidative stress and that alternative mechanisms need to be considered.

Partial Text

Traditional cytotoxic agents remain the mainstay of cancer treatment, despite recent progress in cancer therapeutics with the advent of targeted therapies and immunotherapies. Long-term and late toxicities as a result of anti-cancer treatment are common and may include numerous muscle-related complications such as skeletal muscle weakness and fatigue, cardiomyopathies and other forms of heart disease. Across ages, diagnoses and treatments, the dominant symptom in long-term cancer survivors is fatigue, with increasing recognition that this persisting fatigue may be related to sarcopenia or muscle wasting [1–5].

Understanding of the process by which exposure to Cy results in damage to skeletal muscle and long term impairment in function is limited. Here we demonstrate that a single dose of the alkylating agent Cy in adult mice, compared with saline controlled animals, led to a number of transient (1 day, 1 week) and longer term (6 weeks) skeletal muscle changes. Specifically, 6 weeks after drug administration, we found significant reduction in running capacity. Of note, only the gastrocnemius muscle presented even marginal suggestion of atrophy. Analyses of in vivo mitochondria function showed bio-energetic deficits consistent with impaired mitochondrial function at 1 day and 6 weeks after Cy treatment. The rapid decline in in vivo ATPmax after 1 day may be due to direct inhibition of the mitochondrial electron transport system by the Cy metabolite acrolein [48, 49]. However, the sustained inhibition of ATPmax in the Cy group is likely due to more persistent mechanisms such as disruption of mitochondrial structure resulting from the early toxicity. The absence of an observed effect on respiratory function and mitochondrial content ex vivo despite a decline in in vivo energetics suggests that either 1) the interaction between the cell environment and the mitochondria plays an important role in this Cy-induced dysfunction as we have observed under conditions of oxidative stress and aging skeletal muscle [62, 69] or 2) that in vitro assays performed on permeabilized fibers under saturating substrate concentrations mask more subtle effects on mitochondrial function.

 

Source:

http://doi.org/10.1371/journal.pone.0181086

 

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