Cyclophosphamide leads to persistent deficits in physical performance and in vivo mitochondria function in a mouse model of chemotherapy late effects.
Marie-Laure CrouchGary KnowelsRudolph StuppardNolan G EricsonJason H BielasDavid J MarcinekKaren L SyrjalaPublished in: PloS one (2017)
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.
Keyphrases
- skeletal muscle
- oxidative stress
- low dose
- high dose
- mouse model
- insulin resistance
- high fat diet induced
- drug induced
- cell death
- signaling pathway
- mass spectrometry
- young adults
- amyotrophic lateral sclerosis
- amino acid
- dna damage
- newly diagnosed
- traumatic brain injury
- mental health
- liver failure
- cell proliferation
- electronic health record
- mitochondrial dna
- liquid chromatography tandem mass spectrometry
- emergency department
- inflammatory response
- ms ms
- randomized controlled trial
- diabetic rats
- metabolic syndrome
- copy number
- gene expression
- squamous cell carcinoma
- machine learning
- lps induced
- sleep quality
- pi k akt
- endoplasmic reticulum
- artificial intelligence
- intensive care unit
- acute respiratory distress syndrome
- high resolution
- preterm birth
- high performance liquid chromatography
- tandem mass spectrometry
- data analysis
- nuclear factor
- liquid chromatography