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Chemotherapy has been associated with increased mitochondrial reactive oxygen species production, mitochondrial dysfunction and skeletal muscle atrophy leading to severe patient clinical complications including skeletal muscle fatigue, insulin resistance and wasting. The exact mechanisms behind this skeletal muscle toxicity are largely unknown, and as such co-therapies to attenuate chemotherapy-induced side effects are lacking. Here, we review the current literature describing the clinical manifestations and molecular origins of chemotherapy-induced myopathy with a focus on the mitochondria as the target organelle via which chemotherapeutic agents establish toxicity. We explore the likely mechanisms through which myopathy is induced, using the anthracycline doxorubicin, and the platinum-based alkylating agent oxaliplatin, as examples. Finally, we recommend directions for future research and outline the potential significance of these proposed directions.

The development of clevudine as a treatment for hepatitis B was terminated recently because of case reports of myopathy. In each case, the onset of symptoms occurred between 8 and 13 months after the initiation of treatment. Electromyography and muscle biopsy confirmed the presence of myonecrosis. One report also found evidence of mitochondrial toxicity. The delayed onset and the finding of mitochondrial damage are reminiscent of fialuridine toxicity. Telbivudine has also been reported to be associated with myopathy and neuropathy, particularly when used in combination with pegylated interferon. These findings serve as a sober reminder of the lack of data on long-term safety of nucleos(t)ide analogs for hepatitis B, the importance of balancing benefits versus risks before initiating treatment, and the need for more stringent post-marketing surveillance for drug toxicities.

Introduction of highly active antiretroviral therapy (HAART) has dramatically modified the natural history of HIV disease, but lengthening the survival of HIV-infected individuals has been associated with an increasing prevalence of iatrogenic conditions. Muscular complications of HIV infection are classified as follows: (1) HIV-associated myopathies and related conditions including polymyositis, inclusion-body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis syndrome (DILS), HIV-wasting syndrome, vasculitis, myasthenic syndromes, and chronic fatigue; (2) iatrogenic conditions including mitochondrial myopathies, HIV-associated lipodystrophy syndrome, and immune restoration syndrome; (3) opportunistic infections and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. These features are described in the present review.

Skeletal muscle involvement can occur at all stages of human immunodeficiency virus (HIV) infection, and may represent the first manifestation of the disease. Myopathies in HIV-infected patients are classified as follows: (1) HIV-associated myopathies and related conditions, including HIV polymyositis, inclusion-body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis syndrome (DILS), HIV-wasting syndrome, vasculitic processes, myasthenic syndromes, and chronic fatigue; (2) muscle complications of antiretroviral therapy, including zidovudine and toxic mitochondrial myopathies related to other nucleoside-analogue reverse-transcriptase inhibitors (NRTIs), HIV-associated lipodystrophy syndrome, and immune restoration syndrome related to highly active antiretroviral therapy (HAART); (3) opportunistic infections and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. Introduction of HAART has dramatically modified the natural history of HIV disease by controlling viral replication, but, in turn, lengthening of the survival of HIV-infected individuals has been associated with an increasing prevalence of iatrogenic conditions.

Zidovudine (AZT) can induce a mitochondrial disorder associated with mitochondrial (mt) DNA depletion affecting skeletal muscle, heart, and liver. Zidovudine myopathy is characterized by ragged-red fibers and partial cytochrome c oxidase (COX) deficiency. We evaluated at a single fiber level the expression of COX II (mtDNA-encoded) and COX IV (nuclear DNA-encoded) subunits in 12 HIV-infected patients with zidovudine myopathy. We also evaluated COX activity on longitudinal muscle sections in one patient. In all patients, evaluation of the expression of COX II and COX IV subunits showed focal deficiency. All fibers negative for COX II or COX IV were negative by COX histochemistry; 32-92% (median 61%) of COX-negative fibers were negative for COX II antigens, and 7-58% (median 28%) were negative for COX IV antigens. One hundred and thirty-nine of 317 COX-negative fibers 139 (43.8%) were selectively negative for COX II; 28 of 317 (8.8%) COX-negative fibers were selectively negative for COX IV. A study of longitudinal distribution of COX activity demonstrated that COX deficiency was segmental with blurred borders, as previously observed in patients with myoclonus epilepsy with ragged-red fibers. We conclude that proteins encoded by mtDNA are predominantly, but not exclusively, involved in zidovudine myopathy. Our results confirm the value of single muscle fiber evaluation in the assessment of mitochondrial abnormalities related to zidovudine.

Electromyographic interference patterns during a gradual increase in force were studied by means of the turns-amplitude analysis in a series of HIV-infected patients with and without clinical, biological and histological signs of myopathy. Different parameters were evaluated to determine their sensitivity for the diagnosis of the myopathies that occur in this context. The studied parameters were the number of turns (NT), the mean amplitude of the turns (MA) and the ratio NT/MA (RTA). For each parameter, we compared the interest of mean values, calculated at moderate contraction, to that of peak values. In addition, the shape of the cloud of MA plotted versus NT data points was analyzed. The sensitivity of the turns-amplitude analysis was 95% for the diagnosis of myopathy when NT, MA and RTA were taken together into account, versus 80% in the cloud studies. Peak values were the most sensitive criteria, but mean values abnormalities were observed in some cases of zidovudine myopathy, indicating a potential usefulness of this quantitative EMG method in the differential diagnosis among myopathies in HIV-infected patients.

Muscle biopsies were obtained from 33 consecutive HIV-infected patients with symptoms suggestive of muscle disorder. Twenty-three patients had clinical evidence of myopathy; 18 of these had been taking zidovudine (AZT) for between 8 and 28 months, and were found to have a multifocal necrotizing myopathy with little or no inflammation. However, the remaining five clinically myopathic patients, who had never received AZT or had stopped treatment at least 5 months earlier, had either a necrotizing myopathy which appeared indistinguishable for that seen in patients taking the drug, or an inflammatory myopathy. The 10 clinically non-myopathic patients showed no significant histological abnormalities. Tubuloreticular inclusions (TRI), in capillary endothelial cells, were found in all clinically myopathic cases but were not seen in five out of ten clinically non-myopathic cases. We suggest that AZT causes a myopathy only when an underlying HIV-related inflammatory myopathy is present. The drug appears to substantially reduce the inflammatory reaction in the muscle, but this may recur when the drug is stopped. The appearance of TRI may be the first manifestation of HIV activity in muscle.

Fifty consecutive patients infected with human immunodeficiency virus type 1 (HIV-1) were evaluated regarding the prevalence of HIV-related myopathies and the relevance of zidovudine-related mitochondrial myopathy. Disease stage, total lifetime intake of zidovudine, anthropometric and nutritional parameters, muscle strength, and histochemical and immunohistochemical findings in muscle specimens were recorded. The series was divided into two groups, patients with a total lifetime intake of zidovudine under 200 gm and those with a total lifetime intake over 200 gm. A control group included 50 healthy people matched for age and sex. HIV-related myopathy was defined by the presence of at least one of the classic pathological reactions in muscle, while zidovudine-related myopathy was defined by the presence of ragged red fibers in any percentage. Lower values of the nutritional parameters were detected in the HIV cohort, when compared with normal control values. HIV-related myopathy was detected in 13 (26%) of the 50 patients. There were no differences between groups except for the development of mitochondrial myopathy that occurred in 1 of the 26 patients in Group 1 and in 16 of the 24 in Group II. Six patients who had a total intake of more than 200 gm of zidovudine and demonstrated red ragged fibers in their muscle specimens were absolutely asymptomatic. There was a positive correlation between total intake of zidovudine and the percentage of red ragged fibers in muscle biopsy specimens.