Examining the interplay between cancer, chemotherapy, and skeletal muscle

Abstract

Skeletal muscle is a particularly vulnerable tissue in cancer, as it experiences both cancer- induced wasting and chemotherapy-induced toxicity. Doxorubicin is a commonly used

chemotherapy that can accumulate within skeletal muscle and impair nitric oxide formation and amino acid homeostasis, critical regulators of skeletal muscle health. Exercise may be a potential countermeasure against these negative effects. In addition to this, very little is known about how Doxorubicin impacts muscle when a tumour is present within the system. The purpose of this thesis was to investigate the role of exercise as a countermeasure to Doxorubicin-induced muscle toxicity, as well as the combined effects of a breast cancer model and Doxorubicin on skeletal muscle. This thesis is separated into five studies. Studies 1 and 2 investigated exercise or electrical stimulation on skeletal muscle amino acids, nitric oxide, and drug accumulation following Doxorubicin administration. Studies 3 and 4 investigated the combined effects of breast cancer tumour growth and Doxorubicin administration on skeletal muscle and tumour nitric oxide and drug accumulation, and skeletal muscle, hepatic, neoplastic, and cardiac amino acid pools. Study 5 is a review on skeletal muscle amino acids during cancer cachexia. Study 1 concluded that multiple bouts of whole-body exercise are likely required to reduce

intramuscular drug accumulation (p<0.05), but the exercise was unable to restore Doxorubicin- induced reductions in nitric oxide formation (p>0.05). Glutamate was depleted by Doxorubicin

(p<0.05) and further reduced across all exercise groups (p<0.05). The essential amino acids were also depleted by exercise (p<0.05), highlighting the need for nutritional support when performing exercise following chemotherapy.

Study 2 used isolated electrical stimulation of the hindlimb muscles as an alternative to the vigorous exercise used in study 1. Electrical stimulation did not increase or decrease skeletal muscle Doxorubicin, nitric oxide, or amino acid profiles (p>0.05).

Study 3 quantified changes in skeletal muscle and tumour drug accumulation and nitric oxide following 21, 24, or 28 days of tumour growth with or without Doxorubicin administration. Doxorubicin accumulated equally within muscle both with or without a tumour present. However, Doxorubicinol, a toxic metabolite of the drug, was elevated in muscles of tumour-bearing animals only (p<0.05). Nitric oxide within the muscle did not change throughout tumour growth or Doxorubicin administration. However, tumour nitric oxide was 15-fold higher at day 21 when compared to day 24 or 28 (p<0.05).

Study 4 profiled skeletal muscle, cardiac, hepatic, and tumour amino acid profiles during tumour growth with or without Doxorubicin. Doxorubicin had minimal independent or additive effects on any amino acids. Tumour growth resulted in depleted skeletal muscle glutamate and aspartate (p<0.05) and increased proline (p<0.05). Tumour growth increased liver aspartate (p<0.05) and decreased cardiac glutamate (p<0.05). Interestingly, despite these widespread changes in many tissues, tumour amino acids remained remarkably stable throughout growth (p>0.05), with only some changes following Doxorubicin administration.

Study 5 determined that our understanding of amino acids in cancer cachexia is significantly limited by the heterogeneous methods used to study this and a general lack of human data in the area.