OBJECTIVETo explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system.

METHODSTwelve healthy Sprague-Dawley rats were randomly divided into three equal groups and treated by oral gavage with zidovudine (125 mg/kg/day), adefovir (40 mg/kg/day), or saline (equal volume) for 28 days. The rats' body weights were measured once a week, and blood was collected every two weeks for blood and biochemical tests. All animals were sacrificed at the end of treatment, and liver, kidney, skeletal muscle, and cardiac muscle were collected by necropsy. Mitochondria were isolated from the respective tissue samples, and the activities of respiratory chain complexes were measured. DNA was purified from each sample and the mitochondrial DNA (mtDNA) content was monitored by quantitative real time PCR. Mitochondrial morphology was analyzed under electron microscope.

RESULTSNo significant adverse effects, including body weight loss, abnormal blood or biochemistry, were observed in rats treated with AZT or ADV. The activities of mitochondrial cytochrome c oxidase in liver and cardiac muscle were slightly decreased in rats treated with AZT (liver: 9.44+/-3.09 vs. 17.8+/-12.38, P?=?0.21; cardiac muscle: 32.74+/-5.52 vs. 24.74+/-20.59, P?=?0.28; kidney: 4.42+/-1.53 vs. 14.45+/-13.75, P?=?0.18; skeletal muscle: 33.75+/-8.74 vs. 40.04+/-2.49, P?=?0.45). The mtDNA content was significantly decreased in cardiac muscle of AZT-treated rats (cardiac muscle: 0.15+/-0.13 vs. 0.32+/-0.42, P?=?0.85). The morphology of mitochondria in liver, kidney, skeletal muscle, and cardiac muscle was significantly altered in the AZT-treated rats and included disappearance of the outer membrane, severely damaged structure, and swollen or completely absent cristae. No obvious effects were noted in the ADV- or saline-treated rats.

CONCLUSIONSignificant adverse effects related to mitochondrial toxicity were observed in rats treated with AZT. The slightly decreased mtDNA content in ADV-treated rats may suggest that this antiviral drug can also cause mitochondrial toxic effects.

Adenine ; adverse effects ; analogs & derivatives ; Animals ; DNA, Mitochondrial ; drug effects ; Electron Transport Complex IV ; metabolism ; Female ; Kidney ; enzymology ; Liver ; enzymology ; Mitochondria ; drug effects ; metabolism ; Mitochondria, Heart ; drug effects ; Mitochondria, Liver ; drug effects ; Mitochondria, Muscle ; drug effects ; Muscle, Skeletal ; enzymology ; Myocardium ; enzymology ; Organophosphonates ; adverse effects ; Rats ; Rats, Sprague-Dawley ; Zidovudine ; adverse effects

This study was performed to investigate the subcellular changes of rat atrial muscle cells by immobilization stress. Sprague -Dawley rats weighting 200 gm were immobilized in small round plastic tube for 2, 6, 12, and 24 hours respectively. The atrial tissue obtained from each animals were observed by transmission electron microscopes. In the heart of rat subjected 2 hours immobilization stress no significant morphological changes were found in electron microscopy, similarly as in control animal. After 6 and 12 hours immobilization stress, the following electron -microscopic changes of atrial myocytes were observed at the swelling of mitochondrial matrix with disturbance in cristea, focal loss of cytoplasmic matrix, vacuoles with myeline -like structure, apoptotic changes of myocytes, focal widening of intercalated disc interspace and lysis of myofibrils. After 24 hours immobilization stress, very small sized mitochondria, similarly as small sized secretory granules and various sized granules are observed in the perinuclear region of atrial myocytes. Atrial specific granules are moved centripetally toward the central region of the atrial myocytes after immobilization stress. Above results will be aid in understanding the structures of atrium with dual function of blood circulation and endocrine, and in research of modulation of secretory granules in atrial muscle cells.
Animals ; Blood Circulation ; Cytoplasm ; Heart ; Immobilization* ; Microscopy, Electron ; Mitochondria ; Muscle Cells* ; Myelin Sheath ; Myofibrils ; Plastics ; Rats* ; Secretory Vesicles ; Vacuoles

Short period of ischemia and reperfusion protect heart against subsequent prolonged ischemia-reperfusion injury. This phenomenon was first described by Murry et al in 1986, who demonstrated that four 5-minute coronary artery occlusions followed by equal period of reflow at each time before a subsequent prolonged occlusion resulted in a reduction of infarct size in dog. Although the precise mechanism of preconditioning remains unknown, this phenome-non is present among different species of mammals, including dogs, rats, pigs, rabbits, and human. The objects of present study was to investigate effect of ischemic preconditioning on cell viability, structural changes and apoptosis during 60 min hypoxia and 60 min reoxygenation of the cell. In present study we investigated through cell culture system using myocyte of three days old neonatal rat cultured for three days. During hypoxia and reoxygenation, differences between preconditioned and nonpreconditioned of beating counts, morphological and structural changes are investigated through inverted phase contrast microscope and transmis-sion electron microscope. To detection of apoptotic cell, TUNEL (TdT-mediated dUTP-biotin nick end labeling) stain was accomplished, and through which we invesigate the effects of preconditioning on apoptosis. Viabiliy of each cell and it's mitochondria were measured quantitatively by MTT assay. After 60 min of hypoxia and 60 min of reoxygenation, beating rate decreased remarkably. But at the time of 60 min of reoxygenation, there was marked increase in beating count in pre-conditioned cell. Swollen mitochondria with amorphous granules in inner membrane, destroyed mitochondrial cristae, indented nuclear envelope, chromatin condensation, contracture of myofibril, fragmentation of myofilaments, cytoplasmic shrinkage were observed in both preconditioned cell and nonpreconditioned cell. But it is much less in pre-conditioned cell than in nonpreconditioned cell. MTT activity decreased in both experimental groups in compared with normal group, but in preconditioned group, MTT activity increased markedly in compared with nonpreconditioned group. And apoptosis is decreased by precontitioning in TUNEL staining. These results suggest that cardioprotective effects of ischemic preconditioning is mediated by attenuating structural destroy, increasing cell viability, decreasing apoptosis.
Animals ; Anoxia ; Apoptosis ; Cell Culture Techniques ; Cell Survival ; Chromatin ; Contracture ; Coronary Vessels ; Cytoplasm ; Dogs ; Heart ; Humans ; In Situ Nick-End Labeling ; Ischemia ; Ischemic Preconditioning* ; Mammals ; Membranes ; Mitochondria ; Muscle Cells ; Myocytes, Cardiac* ; Myofibrils ; Nuclear Envelope ; Rabbits ; Rats ; Reperfusion ; Reperfusion Injury ; Swine

Sarcopenia,an age-related disease caused by the imbalance in protein synthesis and degradation,can result in significant decreases in skeletal muscle mass and strength.Skeletal muscle loss during aging is inevitable and can affect the life quality of the elderly.Moreover,it may increase the risks of other age-related diseases in the elderly.However,the underlying molecular mechanism remains unclear in age-related skeletal muscle loss.Autophagy is a degradation pathway for the removal of dysfunctional organelles and damaged macromolecules during aging.Mitochondria also play a key role in skeletal muscle function.To maintain skeletal muscle mass,we should pay attention to autophagy and improve mitochondrial homeostasis through autophagy or other means.This paper summarizes the research progress of autophagy and mitochondrial quality control in sarcopenia,aiming to provide reference for exploring new therapies.
Aged ; Autophagy ; Homeostasis ; Humans ; Mitochondria ; Muscle, Skeletal ; Sarcopenia

Endurance exercise training such as marathon can increase the ability of exercise performance. Muscle glycogen is associated with an exercise performance, because glycogen depletion is primary causes of muscle fatigue. This review summarizes the glycogen saving effect according to duration of endurance exercise training. Long-term endurance exercise-induced mitochondrial biogenesis contributes to glycogen saving effect that is reduced glycogen breakdown and lactate accumulation. Glycogen sparing is due to a smaller decrease in adenosine triphosphate and phosphocreatine and a smaller increase in inorganic phosphate in the working muscles. It takes required endurance exercise training for about 4 weeks or more. Single bout or short-term endurance exercise is not sufficient to bring an increase in functional mitochondria. But peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) increases rapidly after single bout of endurance exercise. PGC-1α downregulates glycogenolytic and glycolytic enzymes to reduce muscle glycogen breakdown and lactic acid accumulation after short-term endurance exercise.
Adenosine Triphosphate ; Glycogen* ; Glycogenolysis ; Lactic Acid ; Mitochondria ; Muscle Fatigue ; Muscle, Skeletal* ; Muscles ; Organelle Biogenesis ; Peroxisomes ; Phosphocreatine

Long-term endurance training or physical activity has been confirmed not only to improve physical performance, but to bring about an obvious beneficial effect on human health; however, the mechanism of this effect is not clear. The most studied health adaptations in skeletal muscle response to endurance exercise are increased muscle glycogen level and insulin sensitivity, fiber type transformation toward oxidative myofibers, and increased mitochondrial content/function. Mitochondria are dynamic organelles in eukaryotic cells critical in physical performance and disease occurrence. The mitochondrial life cycle spans biogenesis, maintenance, and clearance. Exercise training may promote each of these processes and confer positive impacts on skeletal muscle contractile and metabolic functions. This review focused on the regulation of these processes by endurance exercise and discussed its potential benefits in health and disease. We presented evidence suggesting that exercise training potentiates not only the biogenesis of mitochondria but also the removal of old and unhealthy mitochondria through mitochondrial quality control.
Adaptation, Physiological ; Exercise ; Humans ; Mitochondria ; physiology ; Muscle Contraction ; Muscle, Skeletal ; physiology

Insulin resistance in skeletal muscle, liver, beta-cells, fat cells, the gastrointestinal track, alpha-cells, kidneys, and brain represents the core defect in obesity or type 2 diabetes (T2D). Among them, skeletal muscle insulin resistance due to obesity or T2D is manifested by decreased glucose uptake because skeletal muscle comprises 40-50% of the total human body mass. Many previous reports indicate that T2D patients or obese insulin-resistant individuals have less mitochondria in their skeletal muscles than lean control subjects. Whether or not mitochondria in skeletal muscle play a causal role in insulin resistance has been debated. A large number of studies demonstrated that skeletal muscle insulin resistance is associated with mitochondrial deficiency including 1) reduced fatty acid oxidation and increased accumulation of lipid intermediates (e.g., FA-CoA, DAG, ceramide), 2) increased mitochondrial overload and incomplete fatty acid oxidation, and 3) increased mitochondrial oxidative stress (e.g., H2O2) in skeletal muscle. In contrast, some studies demonstrated that mitochondrial dysfunction in skeletal muscle is not responsible for insulin resistance, suggesting that 1) the development of insulin resistance in high-fat diet animals occurs with increased muscle mitochondria, and 2) fatty acid oxidation is higher in T2D patients and obese insulin-resistant individuals compared with lean control subjects. However, various types of exercises (acute vs chronic, aerobic vs resistance) are critical in the treatment and prevention of insulin resistance in obesity and T2D.
Adipocytes ; Animals ; Brain ; Diet, High-Fat ; Exercise ; Glucose ; Human Body ; Humans ; Insulin Resistance ; Kidney ; Liver ; Mitochondria ; Mitochondria, Muscle ; Muscle, Skeletal ; Obesity ; Oxidative Stress

OBJECTIVE: To define the pathologic changes underlying the mechanism of shrinkage of uterine leimyoma in patients treated with goserelin. METHODS: Retrospective evaluation of pathologic changes seen in leiomyoma removed by hysterectomy or myomectomy in treated and untreated patients was done. Microscopic review of all cases was performed without knowledge of the therapeutic history. Each leiomyoma was assessed for hyalinization, hydropic change, lymphocytic infiltrate, nuclear atypia, and hypercellularity. RESULTS: Hyaline degeneration and hydropic changes were found significantly more frequent in patient treated with goserelin (P<0.05). The differences between treated and untreated groups in lymphocytic infiltrate, nuclear atypia, and hypercellularity were not statistically significant. The ultrastructural features of variable numbers of the treated muscle cells showed large vacuole, marked swelling of mitochondria, and compound lysosomal structures presumed to have been formed from damaged intracellular organelles. CONCLUSION: It appears that the rapid decrease in size of the leiomyoma treated with goserein occurs as the smooth muscle tissue undergoes hydropic change and hyaline degeneration. It seems that other cellular degenerative changes may be involved in the mechanism shrinkage of uterine leiomyoma.
Gonadotropin-Releasing Hormone* ; Goserelin* ; Humans ; Hyalin ; Hysterectomy ; Leiomyoma* ; Mitochondria ; Muscle Cells ; Muscle, Smooth ; Organelles ; Retrospective Studies ; Vacuoles

Animals ; Carnitine ; pharmacology ; H(+)-K(+)-Exchanging ATPase ; metabolism ; Mitochondria, Muscle ; enzymology ; Muscle, Skeletal ; drug effects ; Physical Conditioning, Animal ; Rats

OBJECTIVETo study the role of Ca2+ overload and energy metabolism in mitochondria in masticatory muscle dysfunctional induced by occlusal trauma.

METHODSMitochondrial Ca2+ contents were measured with atomic emission spectrophotometer. Mitochondrial ATP and ADP contents were measured with high performance liquid chromatography.

RESULTS(1) Mitochondrial Ca2+ contents of masseter muscle ipsilateral to metal splint in ten and twenty days' experimental groups and that contralateral to metal splint in twenty days' experimental group increased significantly (P < 0.05). (2) Mitochondrial ATP contents of masseter muscle ipsilateral to metal splint in experimental groups were higher than that in control groups and contralateral to metal splint after twenty days. (3) Mitochondrial Ca2+ contents of masseter muscle ipsilateral to metal splint were significantly negatively correlated to the mitochondrial ATP contents (r = -0.780, P < 0.05).

CONCLUSIONCa2+ overload in mitochondria depresses ATP production, which results in energy metabolism disorder in masticatory muscle cells. It may play an important role in the mechanism that occlusal trauma results in masticatory muscle dysfunction.

Adenosine Diphosphate ; chemistry ; Adenosine Triphosphate ; chemistry ; Animals ; Calcium ; chemistry ; Energy Metabolism ; Masseter Muscle ; chemistry ; injuries ; Mitochondria, Muscle ; chemistry ; Rabbits