Doxorubicin stimulates oxidant activity, weakness and fatigue in murine skeletal muscle

Abstract

Doxorubicin is the most commonly prescribed chemotherapeutic agent. Doxorubicin causes an increase in free radical production in the myocardium and cardiac muscle dysfunction. Patients receiving chemotherapy also experience weakness and fatigue leading us to hypothesize doxorubicin (1) increases muscle‐derived oxidants and (2) depresses diaphragm and limb muscle force in mice. Doxorubicin treatment (20μM, 1hr) in vitro increased oxidant activity in diaphragm muscle as measured using DCF fluorescence (n=3, p<0.04). We injected C57B6 male mice intraperitoneally with doxorubicin (20 mg/kg), a cumulative dose commonly used in cardiotoxicity studies. Diaphragm and extensor digitorum longus (EDL) were excised three days post injection, compared to controls, doxorubicin lowered maximal force in diaphragm by 62.2 ± 7.1% (mean ± SE; n=5, p<0.01) and EDL by 28.7 ± 7.9% (n=3, p<0.03). Doxorubicin depressed diaphragm twitch characteristics, including peak force (−37.7 ± 12.5%; n=5, p<0.01) and time to peak force (Doxorubicin 0.15 ± 0.02 N s−1, Control 0.29 ± 0.02 N s−1). At the end of the fatigue trial, force was lower in doxorubicin treated mice 26.9 ± 12.2% of control values. The stability of the muscle in vitro was not altered. Our data shows that doxorubicin causes skeletal muscle weakness and predisposes muscle to fatigue, which may be due to an increase in muscle‐derived oxidants.Supported by: HL 59878 (MBR)