Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress

Abstract

Significance: Fatigue is one of the most common symptoms of cancer and its treatment, manifested in the clinic through weakness and exercise intolerance. These side effects not only compromise patient's quality of life (QOL), but also diminish physical activity, resulting in limited treatment and increased morbidity.

Recent advances: Oxidative stress, mediated by cancer or chemotherapeutic agents, is an underlying mechanism of the drug-induced toxicity. Nontargeted tissues, such as striated muscle, are severely affected by oxidative stress during chemotherapy, leading to toxicity and dysfunction.

Critical issues: These findings highlight the importance of investigating clinically applicable interventions to alleviate the debilitating side effects. This article discusses the clinically available chemotherapy drugs that cause fatigue and oxidative stress in cancer patients, with an in-depth focus on the anthracycline doxorubicin. Doxorubicin, an effective anticancer drug, is a primary example of how chemotherapeutic agents disrupt striated muscle function through oxidative stress.

Future directions: Further research investigating antioxidants could provide relief for cancer patients from debilitating muscle weakness, leading to improved quality of life.

FIG. 1.

Overexpression of the mitochondrial-specific antioxidant MnSOD protects against doxorubicin-induced cardiotoxicity. Electron micrographs of mouse heart 5 days after a single injection of doxorubicin (25 mg/kg). The nontransgenic mouse treated with doxorubicin (control, left) shows variations in mitochondria shape and size, loss of cristae, and exhibits focal swelling. Myofilaments show disarray with loss of Z-bands. The transgenic mouse (transgene, right) that overexpresses human manganese superoxide dismutase (MnSOD) shows uniform mitochondria and intact cardiac myofilaments. Asterisks indicate damaged mitochondria, and M denotes intact mitochondria. The arrow points to intracytoplasmic vacuoles, a nonspecific indicator of cell injury. [From Yen et al. (276); reprinted with permission from the American Society of Clinical Investigation].

FIG. 2.

Doxorubicin depresses skeletal muscle force. Hindlimb muscles were obtained from rats 15 days after daily injections of doxorubicin (1.15 mg/kg/day). Muscles were placed in a tissue bath and isometric contraction measurements were made with a force transducer. Doxorubicin depressed force (N/cm²) in both the EDL (A) and soleus (B) muscles. Open symbols represent the doxorubicin group, closed symbols represent the saline injected controls (n=6–9 muscles for each group). Data are mean±SEM. ^ap<0.05, ^bp<0.01 vs. control. [From Ertunc et al. (71); reprinted with permission from S. Karger AG, Basel].

FIG. 3.

A single injection of doxorubicin depresses force in hindlimb and respiratory muscles. Figure depicts data replotted from recent reports (87, 88) and unpublished observations (L.A. Gilliam). Maximal specific force (N/cm², Po) of soleus (open bars), EDL (hatched bars), and diaphragm (solid bars) was measured 72 h following a single injection of doxorubicin (20 mg/kg) via an intraperitoneal (left) or intravenous (right) injection (n=3–11 per muscle). Data expressed as a percent change of experimental control. Mean values shown±SEM; *p<0.01.

FIG. 4.

Hypothesized pathways for doxorubicin-induced weakness in skeletal muscle. Illustration depicts the two proposed mediators, ROS and TNF, along with hypothesized downstream signaling involved in mediating muscle weakness caused by doxorubicin. ROS, reactive oxygen species; TNF, tumor necrosis factor-alpha; TNFR1, TNF receptor subtype 1.