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Background: Mitochondrial myopathy caused by the long-term use of nucleos(t)ide analogue in patients with chronic hepatitis B (CHB) is mostly characterized by myasthenia and myalgia. Cases with respiratory failure as the prominent manifestation and multisystem symptoms have not been reported., Case Report: We report a case of mitochondrial myopathy associated with the long-term use of entecavir for CHB. The patient was a 54-year-old male who was treated with entecavir for 9 years. During the treatment, hepatitis B virus (HBV) DNA was negative and liver function was normal. However, generalized fatigue, poor appetite, dysosmia and other discomforts gradually presented starting at the 5 th year of treatment, and respiratory failure was the prominent manifestation in the later stage of disease progression. The diagnosis was based on histopathology examination. The dysosmia, hypoxemia and digestive tract symptoms were gradually improved after withdrawal of entecavir., Discussion: Mitochondrial myopathy is a rare side effect of entecavir and can be diagnosed by muscle biopsy. Although the incidence is extremely low, but the severe cases can lead to respiratory failure. We should receive adequate attention in clinical practice., (© 2022. The Author(s).)

Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer frequently leached out from polyvinyl chloride (PVC) products and is quickly metabolized to its monoester equivalent mono(2-ethylhexyl) phthalate (MEHP) once enters organisms. Exposure to DEHP/MEHP through food chain intake has been shown to modified metabolism but its effect on the development of metabolic myopathy of skeletal muscle (SKM) has not been revealed so far. Here, we found that MEHP repressed myogenic terminal differentiation of proliferating myoblasts (PMB) and confluent myoblasts (CMB) but had weak effect on this process once it had been initiated. The transition of mitochondria (MITO) morphology from high efficient filamentary network to low efficient vesicles was triggered by MEHP, implying its negative effects on MITO functions. The impaired MITO functions was further demonstrated by reduced MITO DNA (mtDNA) level and SDH enzyme activity as well as highly increased reactive oxygen species (ROS) in cells after MEHP treatment. The expression of metabolic genes, including PDK4, CPT1b, UCP2, and HO1, was highly increased by MEHP and the promoters of PDK4 and CPT1b were also activated by MEHP. Additionally, the stability of some subunits in the oxidative phosphorylation system (OXPHOS) complexes was found to be reduced by MEHP, implying defective oxidative metabolism in MITO and which was confirmed by repressed palmitic acid oxidation in MEHP-treated cells. Besides, MEHP also blocked insulin-induced glucose uptake. Taken together, our results suggest that MEHP is inhibitory to myogenesis and is harmful to MITO functions in SKM, so its exposure should be avoided or limited., (© 2020 The Author(s).)

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.

Purpose: To report a case of blepharoptosis in a patient with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) with biopsy confirmed mitochondrial deletions consistent with HAART related myopathy., Methods: A 51-year-old man with HIV demonstrated visually significant ptosis after being on HAART therapy for over 20 years., Results: Muscle tissue biopsy following blepharoplasty was analyzed and found to have significant mitochondrial deletions., Conclusions: This patient represents a case of isolated ptosis consistent with acquired myopathy secondary to mitochondrial dysfunction without systemic manifestations otherwise seen in inherited mitochondrial disorders.

Arsenic trioxide (ATO) has been successfully used as a treatment for acute promyelocytic leukemia (APL) for more than a decade. Here we report a patient with APL who developed a mitochondrial myopathy after treatment with ATO. Three months after ATO therapy withdrawal, the patient was unable to walk without assistance and skeletal muscle studies showed a myopathy with abundant cytoplasmic lipid droplets, decreased activities of the mitochondrial respiratory chain complexes, multiple mitochondrial DNA (mtDNA) deletions, and increased muscle arsenic content. Six months after ATO treatment was interrupted, the patient recovered normal strength, lipid droplets had decreased in size and number, respiratory chain complex activities were partially restored, but multiple mtDNA deletions and increased muscle arsenic content persisted. ATO therapy may provoke a delayed, severe, and partially reversible mitochondrial myopathy, and a long-term careful surveillance for muscle disease should be instituted when ATO is used in patients with APL.

The hemolysis of red blood cells and muscle damage results in the release of the heme proteins myoglobin, hemoglobin, and free heme into the vasculature. The mechanisms of heme toxicity are not clear but may involve lipid peroxidation, which we hypothesized would result in mitochondrial damage in endothelial cells. To test this, we used bovine aortic endothelial cells (BAEC) in culture and exposed them to hemin. Hemin led to mitochondrial dysfunction, activation of autophagy, mitophagy, and, at high concentrations, apoptosis. To detect whether hemin induced lipid peroxidation and damaged proteins, we used derivatives of arachidonic acid tagged with biotin or Bodipy (Bt-AA, BD-AA). We found that in cells treated with hemin, Bt-AA was oxidized and formed adducts with proteins, which were inhibited by α-tocopherol. Hemin-dependent mitochondrial dysfunction was also attenuated by α-tocopherol. Protein thiol modification and carbonyl formation occurred on exposure and was not inhibited by α-tocopherol. Supporting a protective role of autophagy, the inhibitor 3-methyladenine potentiated cell death. These data demonstrate that hemin mediates cytotoxicity through a mechanism which involves protein modification by oxidized lipids and other oxidants, decreased respiratory capacity, and a protective role for the autophagic process. Attenuation of lipid peroxidation may be able to preserve mitochondrial function in the endothelium and protect cells from heme-dependent toxicity.

Objective: Peripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathology may be antagonized by uridine supplementation in vivo., Design: Because of the obvious difficulties in obtaining human neural tissues, the mitochondrial neurotoxicity of the nucleoside analogues was studied in mice., Methods: BALB/C mice (7 weeks of age) were fed for 9 weeks with zalcitabine (13 mg/kg per day) or zidovudine (100 mg/kg per day) with or without mitocnol (340 mg/kg per day), a dietary supplement with high uridine bioavailability. Hippocampal and sciatic nerve mitochondria were analyzed., Results: Zalcitabine and to a lesser extent zidovudine induced a significant peripheral neuropathy and encephalopathy with disrupted mitochondrial ultrastructure, depleted mitochondrial DNA, reduced levels of cytochrome c oxidase activity and diminished expression of mitochondrial DNA-encoded cytochrome c oxidase subunit I. Mitocnol had no intrinsic effects but attenuated or fully normalized all measured disorder of the peripheral and central nervous system., Conclusion: Zidovudine and zalcitabine induce a mitochondrial disorder in the peripheral and central nervous system, both of which are antagonized by uridine supplementation.

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.

Unlabelled: Clevudine (Revovir), a pyrimidine nucleoside analogue, is a recently introduced antiviral drug. Clinical trials have demonstrated potent, sustained antiviral activity against hepatitis B virus without specific adverse events. The lack of cytotoxicity and absence of an effect on mitochondrial function have been considered the reasons for the fewer adverse events. However, it came to our attention that several hepatitis B patients developed myopathy during clevudine therapy. Our study was aimed to analyze the clinical and pathological features of patients with clevudine-induced myopathy with some consideration of its pathogenetic mechanism. Seven hepatitis B patients who developed severe skeletal myopathy during clevudine therapy were examined in this study. The demographic data, clinical features, pathological findings, and molecular studies of these patients were analyzed with speculation about the underlying pathogenic mechanisms. All seven patients were treated with clevudine for more than 8 months (8-13 months). In all, the main symptom was slowly progressive proximal muscular weakness over several months. A markedly elevated creatine kinase level and myopathic patterns on electromyography were found. Muscle biopsies revealed severe myonecrosis associated with numerous ragged red fibers, cytochrome c oxidase-negative fibers, and predominant type II fiber atrophy. Molecular studies using quantitative polymerase chain reaction showed a depletion of the mitochondrial DNA in the patients' skeletal muscle., Conclusion: To the best of our knowledge, this is the first report of myopathy associated with clevudine therapy. This study has clearly shown that long-term clevudine therapy can induce the depletion of mitochondrial DNA and lead to mitochondrial myopathy associated with myonecrosis. Careful clinical and laboratory attention should be paid to patients on long-term clevudine therapy for this skeletal muscle dysfunction.

Objective: Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor., Methods: BALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks., Results: Zidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA-encoded cytochrome c oxidase I subunit, but not of nucleus-encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity., Conclusion: Our findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.

The primary goal of the highly active antiretroviral treatment is to improve HIV-infected patient immune function through maintaining viral suppression. However, this treatment may lead to adverse events, some of them potentially serious. This article emphasizes on the antiretroviral therapy associated adverse events and their management recommendations, especially for serious or potentially life-threatening cases. Adverse events analyzed in this article include side effects derived from mitochondrial toxicity, abacavir hypersensitivity reaction, hepatotoxicity, skin rash and Stevens-Johnson syndrome, increased bleeding episodes in hemophilic patients and nephrotoxicity. In some cases, a high suspicion is needed because the onset symptoms may be unspecific.

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.

An asthmatic patient with corticosteroid treatment for 45 years presented with slowly progressive limb muscle atrophy. His muscle symptoms were involved in four limbs and tongue, and deep tendon reflexes were exaggerated. Biopsied muscle pathology indicated the presence of neurogenic muscular atrophy in combination with corticosteroid myopathy. Furthermore, 8-hydroxy-deoxyguanosine (8-OH-dG) was prominently increased in mitochondrial and nuclear DNA. An aerobic exercise test demonstrated remarkable serum lactate elevation, which was attenuated by the administration of coenzyme Q10. These findings are consistent with the assumption that long-term corticosteroid administration potentially induces not only myopathy but also motor neuron involvement as in mitochondrial diseases.

Purpose: This paper discusses the association between inflammatory and mitochondrial pathologies in patients with HIV-1/AIDS treated with zidovudine (AZT)., Methods: We present the clinical and pathological details of a 52-year-old HIV-1 positive male who presented with progressive muscle weakness. We also review the current literature and address the debated pathogenesis of the inflammatory pathology., Results: Muscle biopsy revealed evidence of both HIV-1 polymyositis and AZT myopathy. Six months after initiation of corticosteroid therapy and discontinuation of AZT, the patient's symptoms had greatly improved. The biopsy was repeated to show that both pathologies had resolved., Conclusions: The perceived overlap in the pathological spectra of HIV-1 polymyositis and AZT myopathy has produced some debate on causation and treatment. Unfortunately, there have been very few reports where a repeat biopsy following a drug washout period confirmed resolution of the pathology. Furthermore, affected patients have not been treated in a uniform fashion. Whether this represents one disease or two remains uncertain. The clinical relevance of this issue lies in the potential for harm from the unnecessary use of corticosteroids. This question may be best addressed by a randomized clinical trial.

Objective: The purpose of the study was to build up an animal model of mitochondrial myopathy in order to analyse the pathogenesis of the disease., Methods: The skeletal muscles from Wistar rats treated with germanium dioxide for 24 weeks were analysed by histopathologic and electron-microscopic studies. A quantitative analysis was carried out in mitochondrial DNAs of these samples. The biological function of the model was determined., Results: An animal model of mitochondrial myopathy was built up, in which oxygen free radicals were increased and mitochondrial DNA copies were decreased contrasted with controls., Conclusion: It suggested that environmental toxin may play a role in the pathogenesis of mitochondrial myopathy. The increase of oxygen free radicals is an important link causing the disease.

Nucleoside reverse transcriptase inhibitors (NRTIs) remain the cornerstone of highly active antiretroviral therapy (HAART) combination regimens. However, it has been known for some time that these agents have the potential to cause varied side effects, many of which are thought to be due to their effects on mitochondria. Mitochondria, the key energy generating organelles in the cell, are unique in having their own DNA, a double stranded circular genome of about 16 000 bases. There is a separate enzyme present inside the cell that replicates mitochondrial DNA, polymerase gamma. NRTIs can affect the function of this enzyme and this may lead to depletion of mitochondrial DNA or qualitative changes. The study of inherited mitochondrial diseases has led to further understanding of the consequences of mutations or depletion in mitochondrial DNA. Key among these is the realisation that there may be substantial heteroplasmy among mitochondria within a given cell, and among cells in a particular tissue. The unpredictable nature of mitochondrial segregation during cellular replication makes it difficult to predict the likelihood of dysfunction in a given tissue. In addition, there is a threshold effect for the expression of mitochondrial dysfunction, both at the mitochondrial and cellular level. Various clinical and in vitro studies have suggested that NRTIs are associated with mitochondrial dysfunction in different tissues, although the weight of evidence is limited in many cases. The heterogeneity in the tissues affected by the different drugs raises interesting questions, and possible explanations include differential distribution or activation of these agents. This article reviews the major recognised toxicities associated with NRTI therapy and evidence for mitochondrial dysfunction in these complications. Data were identified through searching of online databases including Medline and Current Contents for relevant articles, along with abstracts and posters from recent conferences in the HIV and mitochondrial fields.

An alert was published during 1999 by the French Perinatal Cohort: eight cases of mitochondrial dysfunction were reported among 1754 infants exposed to nucleoside analogues in utero and during the neonatal period. These eight infants were not infected by HIV. Mitochondrial toxicity of nucleoside analogues is clearly described in adult HIV patients receiving NRTI. Zidovudine (the only and the first NRTI studied) induced mitochondrial DNA dysfunction in animals (monkeys) and neurobehavourial effects in mice at a dose similar to the human dose. Practitioners have been informed. Retrospective and prospective studies are in progress. The recommendations for prevention of maternofoetal transmission of HIV are not reassessed. Pregnant women in rich countries are receiving combination antiretroviral therapy. Information of women has to be undertaken and therapeutic strategies for maternal indication have to be discussed case by case. Careful long term follow up of children exposed to antiretroviral agents is a priority.

Selective nigral degeneration with inclusion formation provoked by systemic administration of the herbicide rotenone, through inhibition of complex I, raises the question of pesticide exposure and environmental factors in general, as a cause of Parkinson's disease (PD). Toxin-induced complex I inhibition probably represents one of many potential causes of PD, but it alerts us to the dangers of such substances in the environment and the need to identify genetically susceptible populations. When vulnerable individuals become known, perhaps they should stay out of the garden.

Recent reports of mitochondrial disease in infants whose mothers were treated in pregnancy with nucleoside analogues are of concern. Chronic nucleoside analogue treatment of adults has long been known to cause mitochondrial DNA depletion with the risk of multisystem disease. Combination nucleoside analogue treatment regimens may have the greatest risk of toxicity. This paper briefly presents the underlying biochemical etiologies and phenotypes of some common genetic mitochondrial diseases in order to provide a comparison with reports of infant toxicity. A standardized method for the diagnosis and evaluation of mitochondrial disease is discussed. A hypothesis, with predictions of the effects of antenatal nucleoside analogue treatment on the fetus, is presented and future directions for research on this problem are suggested.

The rate of advance of our understanding of mitochondrial pathology continues to accelerate. Trends in genotype-phenotype correlations in mitochondrial DNA mutations continue to be developed; the latest of these is the association of exercise intolerance with cytochrome b mutations and onset in infancy of multisystem disorders associated with cytochrome oxidase assembly defects. New models for mitochondrial disease are being developed. Drugs, toxins and deficiency of nuclear encoded proteins that are targeted at mitochondria are now recognized as important causes of secondary mitochondrial respiratory chain deficiency.

Background: An association between use of zidovudine and didanosine and a rare but life-threatening syndrome of hepatic steatosis, lactic acidosis, and myopathy has been reported., Objective: To describe the syndrome of hepatic steatosis, lactic acidosis, and myopathy in four patients taking stavudine., Design: Case series., Setting: A community hospital in Washington, D.C., and National Institutes of Health Clinical Center, Bethesda, Maryland., Patients: Two men and two women with HIV-1 infection who were taking stavudine presented with lactic acidosis and elevated levels of aminotransferases. All patients required intensive care., Measurements: Levels of lactic acid, alanine aminotransferase, aspartate aminotransferase, amylase, and lipase; computed tomography of the abdomen; liver biopsy (two patients); and muscle biopsy (two patients)., Results: Histologic findings consistent with mitochondrial injury confirmed the diagnosis of hepatic or muscle abnormality., Conclusion: Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of elevated hepatic aminotransferase levels among patients taking stavudine.

The chronic administration of S. occidentalis seeds was found to induce a mitochondrial myopathy in hens. This study was undertaken to determine if the chronic treatment with S. occidentalis seeds of rats (as a mammalian model) would induce a mitochondrial myopathy similar to those described in humans and to determine if the histological changes could be correlated with the amount of ingested seeds. Twenty-one days old rats were fed S. occidentalis seeds at different diet concentrations (1, 2, 3%). Rats fed 1% S. occidentalis seeds had only a few COX-negative muscle fibers in the pectoralis major muscle. Rats fed 3% Senna occidentalis seeds had a greater number of COX-negative fibers. Rats fed 2% had an intermediate number of COX-negative fibers. Activity of SDH and NADH-tr were decreased in rats of groups 2% and 3%. Our data indicate that a progressive mitochondrial metabolism impairment can be produced in rats fed S. occidentalis seeds and that this impairment can be correlated with the amount of ingested seeds.

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.

(1) Since 1994, zidovudine administration to pregnant women and their newborns has been the reference prophylaxis for mother-child HIV transmission. (2) Three trials done in Thailand and Africa show that zidovudine therapy during the last few weeks of pregnancy reduces the risk of transmission, especially when breast-feeding is avoided. (3) A retrospective study done in the United States suggests that even very late zidovudine administration may benefit the mother and/or her child. (4) A trial done in Uganda suggests that a single dose of nevirapine has better preventive activity than a very short course of zidovudine in women who breastfeed. (5) There are very few data on the risk-benefit ratio of multidrug antiretroviral regimens in pregnant women. (6) Eight cases of mitochondrial involvement have been diagnosed in France in children exposed to zidovudine or to the zidovudine + lamivudine combination. These cases call for long-term close monitoring of children exposed to antiretroviral drugs in utero. To limit the duration of fetal exposure, the third trimester of pregnancy is now recommended as the safest time to start antiretroviral prophylaxis. (7) Despite a randomised trial and a meta-analysis suggesting that elective caesarean section prevents mother-child HIV transmission, the value of such surgery remains controversial.

3'-azido-3'-deoxythymidine (AZT) is given to pregnant women positive for the human immunodeficiency virus type 1 (HIV-1) to reduce maternal-fetal viral transmission. To explore fetal mitochondrial consequences of this exposure, pregnant Erythrocebus patas monkeys were given daily doses of 1.5 mg (21% of the human daily dose) and 6.0 mg (86% of the human daily dose) of AZT/kg body weight (bw), for the second half of gestation. At term, electron microscopy of fetal cardiac and skeletal muscle showed abnormal and disrupted sarcomeres with myofibrillar loss. Some abnormally shaped mitochondria with disrupted cristae were observed in skeletal muscle myocytes. Oxidative phosphorylation (OXPHOS) enzyme assays showed dose-dependent alterations. At the human-equivalent dose of AZT (6 mg of AZT/kg bw), there was an approximately 85% decrease in the specific activity of NADH dehydrogenase (complex I) and three- to sixfold increases in specific activities of succinate dehydrogenase (complex II) and cytochrome-c oxidase (complex IV). Furthermore, a dose-dependent depletion of mitochondrial DNA levels was observed in both tissues. The data demonstrate that transplacental AZT exposure causes cardiac and skeletal muscle mitochondrial myopathy in the patas monkey fetus.

The issues raised have evolved over the last few years. The rate of mother-to-child transmission has decreased, mostly as a consequence of antiretroviral therapies. However, these drugs can have toxicity such as mitochondrial diseases in the infant, whose incidence and long term consequences are still unknown. The choice of therapy should be based on an estimate of benefit on risk on a case-to-case basis. If the patient requires an effective antiretroviral combination, it should not be withheld because of the pregnancy. If the mother does not require therapy for her own health, prevention of vertical transmission is based on zidovudine monotherapy beginning in the third trimester, which is most effective when combined with elective caesarean delivery. Interdisciplinary care must include clear information in a climate of dialogue with the mother.

Myopathy often complicates Zidovudine (AZT) treatment in patients with acquired immunodeficiency syndrome (AIDS). The pathogenesis of the myopathy is controversial, since clinical phenomena intrinsic to AIDS may interfere per se with the onset of the myopathy. In the present work we investigated the in vivo effect of AZT in an animal model species (rat) not susceptible to HIV infection. Histochemical and electron microscopic analyses demonstrated that, under the experimental conditions used, the in vivo treatment with AZT does not cause in skeletal muscle true dystrophic lesions, but rather mitochondrial alterations confined to the fast fibers. In the same animal models, the biochemical analysis confirmed that mitochondria are the target of AZT toxicity in muscles. The effects of AZT on mitochondria energy transducing mechanisms were investigated in isolated mitochondria both in vivo and in vitro. Membrane potential abnormalities, due to a partial impairment of the respiratory chain capability observed in muscle mitochondria from AZT-treated rats, closely resemble those of control mitochondria in the presence of externally added AZT. mtDNA deletion analysis by PCR amplification and Southern blot analysis did not show any relevant deletion, while mtDNA depletion analysis demonstrated a significant decrease in mtDNA in AZT-treated rats. The present findings show that AZT causes damage to mitochondria by two mechanisms: a short-term mechanism that affects directly the respiratory chain, and a long-term mechanism that alters the mitochondrial DNA thus impairing the mitochondrial protein synthesis. In addition, the ultrastructural observations indicate that the fiber types are differently affected upon AZT treatment, which poses a number of questions as to the pathogenesis of this myopathy.

The purpose of this study were 1) to determine the earliest pathological changes of germanium dioxide (GeO2)-induced myopathy; 2) to determine the pathomechanism of GeO2-induced myopathy; and 3) to determine the minimal dose of GeO2 to induce myopathy in rats. One hundred and twenty five male and female Sprague-Dawley rats, each weighing about 150 gm, were divided into seven groups according to daily doses of GeO2. Within each group, histopathological studies were done at 4, 8, 16, and 24 weeks of GeO2 administration. Characteristic mitochondrial myopathy was induced in the groups treated daily with 10 mg/kg of GeO2 or more. In conclusion, the results were as follows: 1) The earliest pathological change on electron microscope was the abnormalities of mitochondrial shape, size and increased number of mitochondria; 2) The earliest pathological change on light microscope was the presence of ragged red fibers which showed enhanced subsarcolemmal succinate dehydrogenase and cytochrome c oxidase reactivity; 3) GeO2 seemed to affect the mitochondrial oxidative metabolism of muscle fibers; 4) GeO2 could induce mitochondrial myopathy with 10 mg/kg of GeO2 for 4 weeks or less duration in rats.

The use of zidovudine in the treatment of human immunodeficiency virus infection has been associated with toxic mitochondrial myopathy. There are some reported cases of improvement after stopping the drug, but in only one were molecular studies performed. We therefore studied three patients with toxic AZT myopathy during AZT treatment and after drug withdrawal. Clinical complaints disappeared within the next three months after drug cessation. In all cases, histological data of mitochondrial abnormalities also disappeared. Molecular studies showed an initial depletion of the total amount of mitochondrial DNA with respect to healthy controls which was reversible after AZT withdrawal. This work demonstrates that AZT myopathy is reversible not only at a clinical and histological, but also at a molecular level.

Plants of the genus Senna (formerly Cassia) have been recognized as the cause of a natural and experimental syndrome of muscle degeneration frequently leading to death in animals. Histologically, it demonstrated skeletal and cardiac muscle necrosis, with floccular degeneration and proliferation of sarcolemmal nuclei. Recently, it was described as an experimental model of mitochondrial myopathy in hens chronically treated with Senna occidentalis. Currently, skeletal muscles of chicks intoxicated with seeds of the poisonous plant S. occidentalis were studied by histochemistry and electron microscopy. Since birth, the birds were fed ground dried seeds of this plant with a regular chicken ration at a dose of 4% for 11 days. Microscopic examination revealed, besides muscle-fiber atrophy, lipid storage in most fibers and a moderate amount of cytochrome oxidase-negative fibers. By electron microscopy, enlarged mitochondria with disrupted or excessively branched cristae were seen. This picture was characteristic of mitochondrial myopathy. These findings have hitherto remained unnoticed in skeletal muscle of young birds treated with S. occidentalis.

Introduction: Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) Reductase inhibitors are a group of drugs widely used for hypercholesterolemia. They are known to originate side-effects on muscles but with a very low incidence of myopathy., Clinical Case: We present two cases of myopathy induced by HMG-CoA reductase inhibitors. They are two women, who were on 20 mg daily of lovastatin and 30 mg daily of simvastatin and consulted due to weakness, myalgia and a rise in blood levels of muscle enzymes. Both of them recovered completely a few weeks after withdrawal of the drugs., Comments: Usage of this group of drugs is wide. Their side effects are rare but it is important to remember their capacity to induce a myopathy, usually reversible upon withdrawal of the drug.

A 21 year old male ingested podophyllin in a suicide attempt. The disorder was marked by seizures, coma, peripheral neuropathy, renal failure and acute necrotizing myopathy, an unusual finding. The coma and systemic disturbances resolved within three weeks. The myopathy resolved in 7 weeks, demonstrating a high capacity of muscle recuperation. The sensorimotor peripheral neuropathy persisted until the patient's death 9 weeks after the ingestion, due to septicemia. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin, and describes a reversible necrotizing myopathy associated to mitochondrial abnormalities, a still unreported feature of podophyllin toxicity.

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.