Effect of fluoxetine treatment on mitochondrial bioenergetics in central and peripheral rat tissues

2015 ◽  
Vol 40 (6) ◽  
pp. 565-574 ◽  
Author(s):  
Aline Isabel da Silva ◽  
Glauber Ruda Feitoza Braz ◽  
Reginaldo Silva-Filho ◽  
Anderson Apolonio Pedroza ◽  
Diorginis Soares Ferreira ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Diseases ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Wistar Rat ◽  
Male Rats ◽  
Mitochondrial Activity ◽  
Rat Tissues ◽  
Transferase Activity ◽  
Mitochondrial Bioenergetics

Recent investigations have focused on the mitochondrion as a direct drug target in the treatment of metabolic diseases (obesity, metabolic syndrome). Relatively few studies, however, have explicitly investigated whether drug therapies aimed at changing behavior by altering central nervous system (CNS) function affect mitochondrial bioenergetics, and none has explored their effect during early neonatal development. The present study was designed to evaluate the effects of chronic treatment of newborn male rats with the selective serotonin reuptake inhibitor fluoxetine on the mitochondrial bioenergetics of the hypothalamus and skeletal muscle during the critical nursing period of development. Male Wistar rat pups received either fluoxetine (Fx group) or vehicle solution (Ct group) from the day of birth until 21 days of age. At 60 days of age, mitochondrial bioenergetics were evaluated. The Fx group showed increased oxygen consumption in several different respiratory states and reduced production of reactive oxygen species, but there was no change in mitochondrial permeability transition pore opening or oxidative stress in either the hypothalamus or skeletal muscle. We observed an increase in glutathione S-transferase activity only in the hypothalamus of the Fx group. Taken together, our results suggest that chronic exposure to fluoxetine during the nursing phase of early rat development results in a positive modulation of mitochondrial respiration in the hypothalamus and skeletal muscle that persists into adulthood. Such long-lasting alterations in mitochondrial activity in the CNS, especially in areas regulating appetite, may contribute to permanent changes in energy balance in treated animals.

Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle

2007 ◽  
Vol 292 (3) ◽  
pp. E748-E755 ◽  
Author(s):  
Peter J. Adhihetty ◽  
Vladimir Ljubicic ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Manganese Superoxide Dismutase ◽  
Mitochondrial Permeability Transition ◽  
Contractile Activity ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Production ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Chronic contractile activity of skeletal muscle induces an increase in mitochondria located in proximity to the sarcolemma [subsarcolemmal (SS)] and in mitochondria interspersed between the myofibrils [intermyofibrillar (IMF)]. These are energetically favorable metabolic adaptations, but because mitochondria are also involved in apoptosis, we investigated the effect of chronic contractile activity on mitochondrially mediated apoptotic signaling in muscle. We hypothesized that chronic contractile activity would provide protection against mitochondrially mediated apoptosis despite an elevation in the expression of proapoptotic proteins. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 h/day) rat muscle for 7 days. Chronic contractile activity did not alter the Bax/Bcl-2 ratio, an index of apoptotic susceptibility, and did not affect manganese superoxide dismutase levels. However, contractile activity increased antiapoptotic 70-kDa heat shock protein and apoptosis repressor with a caspase recruitment domain by 1.3- and 1.4-fold ( P < 0.05), respectively. Contractile activity elevated SS mitochondrial reactive oxygen species (ROS) production 1.4- and 1.9-fold ( P < 0.05) during states IV and III respiration, respectively, whereas IMF mitochondrial state IV ROS production was suppressed by 28% ( P < 0.05) and was unaffected during state III respiration. Following stimulation, exogenous ROS treatment produced less cytochrome c release (25–40%) from SS and IMF mitochondria, and also reduced apoptosis-inducing factor release (≈30%) from IMF mitochondria, despite higher inherent cytochrome c and apoptosis-inducing factor expression. Chronic contractile activity did not alter mitochondrial permeability transition pore (mtPTP) components in either subfraction. However, SS mitochondria exhibited a significant increase in the time to Vmax of mtPTP opening. Thus, chronic contractile activity induces predominantly antiapoptotic adaptations in both mitochondrial subfractions. Our data suggest the possibility that chronic contractile activity can exert a protective effect on mitochondrially mediated apoptosis in muscle.

scholarly journals Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies

2019 ◽  
Vol 316 (3) ◽  
pp. C449-C455 ◽  
Author(s):  
Sofhia V. Ramos ◽  
Meghan C. Hughes ◽  
Christopher G. R. Perry
Keyword(s):  
Skeletal Muscle ◽  
Direct Interaction ◽  
Permeability Transition Pore ◽  
Anion Channel ◽  
Permeability Transition ◽  
Mitochondrial Bioenergetics ◽  
Voltage Dependent Anion Channel ◽  
Retention Capacity ◽  
Microtubule Stabilization

Microtubule-targeting chemotherapies are linked to impaired cellular metabolism, which may contribute to skeletal muscle dysfunction. However, the mechanisms by which metabolic homeostasis is perturbed remains unknown. Tubulin, the fundamental unit of microtubules, has been implicated in the regulation of mitochondrial-cytosolic ADP/ATP exchange through its interaction with the outer membrane voltage-dependent anion channel (VDAC). Based on this model, we predicted that disrupting microtubule architecture with the stabilizer paclitaxel and destabilizer vinblastine would impair skeletal muscle mitochondrial bioenergetics. Here, we provide in vitro evidence of a direct interaction between both α-tubulin and βII-tubulin with VDAC2 in untreated single extensor digitorum longus (EDL) fibers. Paclitaxel increased both α- and βII-tubulin-VDAC2 interactions, whereas vinblastine had no effect. Utilizing a permeabilized muscle fiber bundle preparation that retains the cytoskeleton, paclitaxel treatment impaired the ability of ADP to attenuate H2O2 emission, resulting in greater H2O2 emission kinetics. Despite no effect on tubulin-VDAC2 binding, vinblastine still altered mitochondrial bioenergetics through a surprising increase in ADP-stimulated respiration while also impairing ADP suppression of H2O2 and increasing mitochondrial susceptibility to calcium-induced formation of the proapoptotic permeability transition pore. Collectively, these results demonstrate that altering microtubule architecture with chemotherapeutics disrupts mitochondrial bioenergetics in EDL skeletal muscle. Specifically, microtubule stabilization increases H2O2 emission by impairing ADP sensitivity in association with greater tubulin-VDAC binding. In contrast, decreasing microtubule abundance triggers a broad impairment of ADP’s governance of respiration and H2O2 emission as well as calcium retention capacity, albeit through an unknown mechanism.

Apoptosis in Heart and Skeletal Muscle

2002 ◽  
Vol 27 (4) ◽  
pp. 349-395 ◽  
Author(s):  
Andy J. Primeau ◽  
Peter J. Adhihetty ◽  
David A. Hood
Keyword(s):  
Reactive Oxygen Species ◽  
Skeletal Muscle ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Permeability Transition ◽  
Current Evidence ◽  
Oxygen Species ◽  
Cellular Mechanisms

Apoptosis, or programmed cell death, is now recognized to be an important cellular event during normal development and in the progression of specific diseases. Apoptosis can be triggered by stimuli initiating outside of the cell, or within the mitochondria, leading to the activation of caspases and subsequent cell death. Although apoptosis has been widely studied in a variety of tissues over the last 5 years, skeletal muscle and heart have been relatively ignored in this regard. Research on apoptosis in cardiac muscle has recently taken on a higher profile as the recognition emerges that it may be an important contributor to specific cardiac pathologies, particularly in response to ischemia-reperfusion in which reactive oxygen species are formed. In skeletal muscle, very few studies have been done under specific physiological (e.g., exercise) and pathophysiological (e.g., dystrophies, denervation, myopathies) conditions. Skeletal muscle is unique in that it is mutli-nucleated, and evidence suggests that it can undergo individual myonuclear apoptosis as well as complete cell death. This review discusses the basic cellular mechanisms of apoptosis, as well as the current evidence of this process in cardiac and skeletal muscle. The need for more work in this area is highlighted, particularly in exercise and training. Key words: transcription factors, reactive oxygen species, mitochondria, caspase, mitochondrial permeability transition

Cardioprotection of the aged rat heart by GSK-3β inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation

2011 ◽  
Vol 300 (3) ◽  
pp. H922-H930 ◽  
Author(s):  
Jiang Zhu ◽  
Mario J. Rebecchi ◽  
Peter S. A. Glass ◽  
Peter R. Brink ◽  
Lixin Liu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Male Rats ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

It is well established that inhibition of glycogen synthase kinase (GSK)-3β in the young adult myocardium protects against ischemia-reperfusion (I/R) injury through inhibition of mitochondrial permeability transition pore (mPTP) opening. Here, we investigated age-associated differences in the ability of GSK-3β inhibitor [SB-216763 (SB)] to protect the heart and to modulate mPTP opening during I/R injury. Fischer 344 male rats were assigned from their respective young or old age groups. Animals were subjected to 30 min ischemia following 120 min reperfusion to determine myocardial infarction (MI) size in vivo. Ischemic tissues were collected 10 min after reperfusion for nicotinamide adenine dinucleotide (NAD+) measurements and immunoblotting. In parallel experiments, ventricular myocytes isolated from young or old rats were exposed to oxidative stress through generation of reactive oxygen species (ROS), and mPTP opening times were measured by using confocal microscopy. Our results showed that SB decreased MI in young SB-treated rats compared with young untreated I/R animals, whereas SB failed to significantly affect MI in the old animals. SB also significantly increased GSK-3β phosphorylation in young rats, but phosphorylation levels were already highly elevated in old control groups. There were no significant differences observed between SB-treated and untreated old animals. NAD+levels were better maintained in young SB-treated animals compared with the young untreated group during I/R, but this relative improvement was not observed in old animals. SB also significantly prolonged the time to mPTP opening induced by ROS in young cardiomyocytes, but not in aged cardiomyocytes. These results demonstrate that this GSK-3β inhibitor fails to protect the aged myocardium in response to I/R injury or prevent mPTP opening following a rise in ROS and suggest that healthy aging alters mPTP regulation by GSK-3β.

BDE-154 Induces Mitochondrial Permeability Transition and Impairs Mitochondrial Bioenergetics

2014 ◽  
Vol 77 (1-3) ◽  
pp. 24-36 ◽  
Author(s):  
Lílian Cristina Pereira ◽  
Luiz Felippe Cabral Miranda ◽  
Alecsandra Oliveira de Souza ◽  
Daniel Junqueira Dorta
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Permeability

High Throughput Fluorescence Assays for the Measurement of Mitochondrial Activity in Intact Human Neuroblastoma Cells

2001 ◽  
Vol 6 (6) ◽  
pp. 413-420 ◽  
Author(s):  
Anthony J. Woollacott ◽  
Peter B. Simpson
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Neuroblastoma Cells ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Rapid Screening ◽  
Mitochondrial Activity ◽  
Imaging Plate ◽  
Human Neuroblastoma ◽  
Mitochondrial Permeability ◽  
Compound Libraries

The mitochondrial permeability transition event is implicated in the activation phase of apoptosis and necrosis, and is therefore postulated to play a role in many disease states. Mitochondrial permeability transition is therefore of increasing pharmaceutical interest. Drug discovery requires the rapid screening of compound libraries to identify functionally active ligands. We report the development of two fluorescence-based approaches for screening compound libraries for effects on mitochondrial function. These assays use the fluorometric imaging plate reader in 96-well format, and two commercially available dyes: JC-1 and calcein-AM. We show here that a JC-1 assay proved highly amenable to HTS implementation. By combining this with a calcein-based assay, these approaches gave complementary information: JC-1 facilitates the discovery of modulators of mitochondrial polarization from a library of -100,000 compounds screened at 8 1μM, and the calcein assay identifies permeability transition pore-specific inhibitors.

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