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.
Highlights
Traditional cytotoxic agents remain the mainstay of cancer treatment, despite recent progress in cancer therapeutics with the advent of targeted therapies and immunotherapies
A number of studies have shown that compared to non-cancer controls, breast cancer survivors have higher rates of appendicular muscle mass loss which correlates with higher levels of fasting insulin, decreased bone density, decreased physical function, and increased risk of early frailty and all-cause mortality [10,11,12,13,14,15,16,17,18]
Similar findings are apparent for survivors of prostate cancer who are on androgen deprivation therapy, recipients of hematopoietic stem cell transplant (HCT), and survivors of childhood cancers [19,20,21,22,23,24]
Summary
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. 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 [1,2,3,4,5]. Acquired skeletal muscle weakness and atrophy after cancer and its treatment is associated with increased morbidity and mortality in cancer survivors [6,7,8,9]. Similar findings are apparent for survivors of prostate cancer who are on androgen deprivation therapy, recipients of hematopoietic stem cell transplant (HCT), and survivors of childhood cancers [19,20,21,22,23,24]
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