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Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction.
Gilliam LA, Lark DS, Reese LR, Torres MJ, Ryan TE, Lin CT, Cathey BL, Neufer PD
(2016) Am J Physiol Endocrinol Metab 311: E293-301
MeSH Terms: Animals, Antineoplastic Agents, Breast Neoplasms, Catalase, Disease Models, Animal, Doxorubicin, Electron Transport Complex I, Electron Transport Complex II, Female, Hydrogen Peroxide, Mice, Mice, Transgenic, Mitochondria, Muscle, Muscle Contraction, Muscle, Skeletal, Oxidation-Reduction, Proteins
Show Abstract · Added October 17, 2016
The loss of strength in combination with constant fatigue is a burden on cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and increases mitochondrial H2O2 We hypothesized that the combined effect of cancer and chemotherapy in an immunocompetent breast cancer mouse model (E0771) would compromise skeletal muscle mitochondrial respiratory function, leading to an increase in H2O2-emitting potential and impaired muscle function. Here, we demonstrate that cancer chemotherapy decreases mitochondrial respiratory capacity supported with complex I (pyruvate/glutamate/malate) and complex II (succinate) substrates. Mitochondrial H2O2-emitting potential was altered in skeletal muscle, and global protein oxidation was elevated with cancer chemotherapy. Muscle contractile function was impaired following exposure to cancer chemotherapy. Genetically engineering the overexpression of catalase in mitochondria of muscle attenuated mitochondrial H2O2 emission and protein oxidation, preserving mitochondrial and whole muscle function despite cancer chemotherapy. These findings suggest mitochondrial oxidants as a mediator of cancer chemotherapy-induced skeletal muscle dysfunction.
Copyright © 2016 the American Physiological Society.
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17 MeSH Terms
CKD and Muscle Mitochondrial Energetics.
Roshanravan B, Kestenbaum B, Gamboa J, Jubrias SA, Ayers E, Curtin L, Himmelfarb J, de Boer IH, Conley KE
(2016) Am J Kidney Dis 68: 658-659
MeSH Terms: Adenosine Triphosphate, Adult, Aged, Case-Control Studies, Energy Metabolism, Female, Humans, Magnetic Resonance Spectroscopy, Male, Middle Aged, Mitochondria, Muscle, Muscle, Skeletal, Optical Imaging, Oxygen Consumption, Renal Insufficiency, Chronic, Spectrum Analysis
Added October 28, 2016
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16 MeSH Terms
CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.
Cappel DA, Lantier L, Palmisano BT, Wasserman DH, Stafford JM
(2015) PLoS One 10: e0136915
MeSH Terms: Animals, Cholesterol Ester Transfer Proteins, Diet, High-Fat, Female, Gene Expression Regulation, Glutamic Acid, Humans, Malates, Mice, Mitochondria, Muscle, Obesity, Oxidation-Reduction, Physical Conditioning, Animal
Show Abstract · Added September 28, 2015
Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.
1 Communities
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13 MeSH Terms
Enhanced mitochondrial superoxide scavenging does not improve muscle insulin action in the high fat-fed mouse.
Lark DS, Kang L, Lustig ME, Bonner JS, James FD, Neufer PD, Wasserman DH
(2015) PLoS One 10: e0126732
MeSH Terms: Animals, Diet, High-Fat, Insulin, Mice, Mice, Inbred C57BL, Mitochondria, Muscle, Muscle, Skeletal, Signal Transduction, Superoxides
Show Abstract · Added September 28, 2015
Improving mitochondrial oxidant scavenging may be a viable strategy for the treatment of insulin resistance and diabetes. Mice overexpressing the mitochondrial matrix isoform of superoxide dismutase (sod2(tg) mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcat(tg) mice) have increased scavenging of O2(˙-) and H2O2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat(tg) mice. The goal of the current study was to test the hypothesis that increased O2(˙-) scavenging alone or in combination with increased H2O2 scavenging (mtAO mice) enhances in vivo muscle insulin action in the HF-fed mouse. Insulin action was examined in conscious, unrestrained and unstressed wild type (WT), sod2(tg), mcat(tg) and mtAO mice using hyperinsulinemic-euglycemic clamps (insulin clamps) combined with radioactive glucose tracers following sixteen weeks of normal chow or HF (60% calories from fat) feeding. Glucose infusion rates, whole body glucose disappearance, and muscle glucose uptake during the insulin clamp were similar in chow- and HF-fed WT and sod2(tg) mice. Consistent with our previous work, HF-fed mcat(tg) mice had improved muscle insulin action, however, an additive effect was not seen in mtAO mice. Insulin-stimulated Akt phosphorylation in muscle from clamped mice was consistent with glucose flux measurements. These results demonstrate that increased O2(˙-) scavenging does not improve muscle insulin action in the HF-fed mouse alone or when coupled to increased H2O2 scavenging.
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9 MeSH Terms
Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit.
Fisher-Wellman KH, Lin CT, Ryan TE, Reese LR, Gilliam LA, Cathey BL, Lark DS, Smith CD, Muoio DM, Neufer PD
(2015) Biochem J 467: 271-80
MeSH Terms: Animals, Enzyme Inhibitors, Hydrogen Peroxide, Membrane Potential, Mitochondrial, Mice, Mitochondria, Muscle, Mitochondrial Proteins, NADP, NADP Transhydrogenase, AB-Specific, Oxidation-Reduction, Pyruvate Dehydrogenase Complex
Show Abstract · Added January 26, 2016
Cellular proteins rely on reversible redox reactions to establish and maintain biological structure and function. How redox catabolic (NAD+/NADH) and anabolic (NADP+/NADPH) processes integrate during metabolism to maintain cellular redox homoeostasis, however, is unknown. The present work identifies a continuously cycling mitochondrial membrane potential (ΔΨm)-dependent redox circuit between the pyruvate dehydrogenase complex (PDHC) and nicotinamide nucleotide transhydrogenase (NNT). PDHC is shown to produce H2O2 in relation to reducing pressure within the complex. The H2O2 produced, however, is effectively masked by a continuously cycling redox circuit that links, via glutathione/thioredoxin, to NNT, which catalyses the regeneration of NADPH from NADH at the expense of ΔΨm. The net effect is an automatic fine-tuning of NNT-mediated energy expenditure to metabolic balance at the level of PDHC. In mitochondria, genetic or pharmacological disruptions in the PDHC-NNT redox circuit negate counterbalance changes in energy expenditure. At the whole animal level, mice lacking functional NNT (C57BL/6J) are characterized by lower energy-expenditure rates, consistent with their well-known susceptibility to diet-induced obesity. These findings suggest the integration of redox sensing of metabolic balance with compensatory changes in energy expenditure provides a potential mechanism by which cellular redox homoeostasis is maintained and body weight is defended during periods of positive and negative energy balance.
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11 MeSH Terms
Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload.
Fisher-Wellman KH, Gilliam LAA, Lin CT, Cathey BL, Lark DS, Darrell Neufer P
(2013) Free Radic Biol Med 65: 1201-1208
MeSH Terms: Adult, Animals, Female, Glutathione, Humans, Hydrogen Peroxide, Male, Mice, Mice, Inbred C57BL, Mitochondria, Muscle, NAD, Oxidation-Reduction, Pyruvate Dehydrogenase Complex, Rats, Rats, Sprague-Dawley, Respiration, Superoxides
Show Abstract · Added January 23, 2015
Once regarded as a "by-product" of aerobic metabolism, the production of superoxide/H2O2 is now understood to be a highly specialized and extensively regulated process responsible for exerting control over a vast number of thiol-containing proteins, collectively referred to as the redox-sensitive proteome. Although disruptions within this process, secondary to elevated peroxide exposure, have been linked to disease, the sources and mechanisms regulating increased peroxide burden remain poorly defined and as such are difficult to target using pharmacotherapy. Here we identify the pyruvate dehydrogenase complex (PDC) as a key source of H2O2 within skeletal muscle mitochondria under conditions of depressed glutathione redox buffering integrity. Treatment of permeabilized myofibers with varying concentrations of the glutathione-depleting agent 1-chloro-2,4-dinitrobenzene led to a dose-dependent increase in pyruvate-supported JH2O2 emission (the flux of H2O2 diffusing out of the mitochondrial matrix into the surrounding assay medium), with emission rates eventually rising to exceed those of all substrate combinations tested. This striking sensitivity to glutathione depletion was observed in permeabilized fibers prepared from multiple species and was specific to PDC. Physiological oxidation of the cellular glutathione pool after high-fat feeding in rodents was found to elevate PDC JH2O2 emission, as well as increasing the sensitivity of the complex to GSH depletion. These findings reveal PDC as a potential major site of H2O2 production that is extremely sensitive to mitochondrial glutathione redox status.
Published by Elsevier Inc.
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17 MeSH Terms
Early depression of Ankrd2 and Csrp3 mRNAs in the polyribosomal and whole tissue fractions in skeletal muscle with decreased voluntary running.
Roberts MD, Childs TE, Brown JD, Davis JW, Booth FW
(2012) J Appl Physiol (1985) 112: 1291-9
MeSH Terms: Adaptation, Physiological, Animals, Fatty Acids, Female, LIM Domain Proteins, Mitochondria, Muscle, Models, Animal, Muscle Proteins, Muscle, Skeletal, Polyribosomes, RNA, Messenger, Rats, Rats, Wistar, Running, Time Factors
Show Abstract · Added October 23, 2017
The wheel-lock (WL) model for depressed ambulatory activity in rats has shown metabolic maladies ensuing within 53-173 h after WL begins. We sought to determine if WL beginning after 21-23 days of voluntary running in growing female Wistar rats affected the mRNA profile in the polyribosomal fraction from plantaris muscle shortly following WL. In experiment 1, WL occurred at 0200 and muscles were harvested at 0700 daily at 5 h (WL5h, n = 4), 29 h (WL29h, n = 4), or 53 h (WL53h, n = 4) after WL. Affymetrix Rat Gene 1.0 ST Arrays were used to test the initial question as to whether WL affects mRNA occupancy on skeletal muscle polyribosomes. Using a false discovery rate of 15%, no changes in mRNAs in the polyribosomal fraction were observed at WL29h and eight mRNAs (of over 8,200 identified targets) were altered at WL53h compared with WL5h. Interestingly, two of the six downregulated genes included ankyrin repeat domain 2 (Ankrd2) and cysteine-rich protein 3/muscle LIM protein (Csrp3), both of which encode mechanical stretch sensors and RT-PCR verified their WL-induced decline. In experiment 2, whole muscle mRNA and protein levels were analyzed for Ankrd2 and Csrp3 from the muscles of WL5h (4 original samples + 2 new), WL29h (4 original), WL53h (4 original + 2 new), as well as WL173 h (n = 6 new) and animals that never ran (SED, 4-5 new). Relative to WL5h controls, whole tissue Ankrd2 and Csrp3 mRNAs were lower (P < 0.05) at WL53h, WL173h, and SED; Ankrd2 protein tended to decrease at WL53h (P = 0.054) and Csrp3 protein was less in WL173h and SED rats (P < 0.05). In summary, unique early declines in Ankrd2 and Csrp3 mRNAs were identified with removal of voluntary running, which was subsequently followed by declines in Csrp3 protein levels during longer periods of wheel lock.
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15 MeSH Terms
Muscle endurance and mitochondrial function after chronic normobaric hypoxia: contrast of respiratory and limb muscles.
Gamboa JL, Andrade FH
(2012) Pflugers Arch 463: 327-38
MeSH Terms: Animals, Diaphragm, Hypoxia, Ion Channels, Lower Extremity, Male, Mice, Mice, Inbred C57BL, Mitochondria, Muscle, Mitochondrial Proteins, Models, Animal, Muscle Fatigue, Muscle Fibers, Skeletal, Muscle Strength, Oxygen Consumption, Physical Endurance, Respiratory Muscles, Time Factors, Uncoupling Protein 3, Upper Extremity
Show Abstract · Added April 25, 2016
Skeletal muscle adaptation to chronic hypoxia includes loss of oxidative capacity and decrease in fiber size. However, the diaphragm may adapt differently since its activity increases in response to hypoxia. Thus, we hypothesized that chronic hypoxia would not affect endurance, mitochondrial function, or fiber size in the mouse diaphragm. Adult male mice were kept in normoxia (control) or hypoxia (hypoxia, FIO(2) = 10%) for 4 weeks. After that time, muscles were collected for histological, biochemical, and functional analyses. Hypoxia soleus muscles fatigued faster (fatigue index higher in control, 21.5 ± 2.6% vs. 13.4 ± 2.4%, p < 0.05), but there was no difference between control and hypoxia diaphragm bundles. Mean fiber cross-sectional area was unchanged in hypoxia limb muscles, but it was 25% smaller in diaphragm (p < 0.001). Ratio of capillary length contact to fiber perimeter was significantly higher in hypoxia diaphragm (28.6 ± 1.2 vs. 49.3 ± 1.4, control and hypoxia, p < 0.001). Mitochondrial respiration rates in hypoxia limb muscles were lower: state 2 decreased 19%, state 3 31%, and state 4 18% vs. control, p < 0.05 for all comparisons. There were similar changes in hypoxia diaphragm: state 3 decreased 29% and state 4 17%, p < 0.05. After 4 weeks of hypoxia, limb muscle mitochondria had lower content of complex IV (cytochrome c oxidase), while diaphragm mitochondria had higher content of complexes IV and V (F (1)/F (0) ATP synthase) and less uncoupling protein 3 (UCP-3). These data demonstrate that diaphragm retains its endurance during chronic hypoxia, apparently due to a combination of morphometric changes and optimization of mitochondrial energy production.
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20 MeSH Terms
Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis.
Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP
(2012) Biochim Biophys Acta 1822: 185-95
MeSH Terms: AMP-Activated Protein Kinases, Animals, Berberine, Cell Line, Diet, High-Fat, Glucose, Hormones, Hyperglycemia, Insulin Resistance, Male, Mice, Mitochondria, Mitochondria, Muscle, Muscle, Skeletal, Myoblasts, NAD, Obesity, Organelle Biogenesis, Phosphorylation, Rats, Rats, Sprague-Dawley, Sirtuin 1
Show Abstract · Added April 25, 2013
Berberine (BBR) has recently been shown to improve insulin sensitivity in rodent models of insulin resistance. Although this effect was explained partly through an observed activation of AMP-activated protein kinase (AMPK), the upstream and downstream mediators of this phenotype were not explored. Here, we show that BBR supplementation reverts mitochondrial dysfunction induced by High Fat Diet (HFD) and hyperglycemia in skeletal muscle, in part due to an increase in mitochondrial biogenesis. Furthermore, we observe that the prevention of mitochondrial dysfunction by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells in which SIRT1 has been knocked-down. Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance.
Copyright © 2011 Elsevier B.V. All rights reserved.
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22 MeSH Terms
Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle.
Perry CG, Kane DA, Lin CT, Kozy R, Cathey BL, Lark DS, Kane CL, Brophy PM, Gavin TP, Anderson EJ, Neufer PD
(2011) Biochem J 437: 215-22
MeSH Terms: Adenosine Diphosphate, Adult, Animals, Creatine, Heterocyclic Compounds, 4 or More Rings, Humans, Male, Mitochondria, Muscle, Muscle Contraction, Muscle Fibers, Skeletal, Muscle, Skeletal, Myosins, Phosphocreatine, Rats, Respiration, Temperature
Show Abstract · Added January 23, 2015
Assessment of mitochondrial ADP-stimulated respiratory kinetics in PmFBs (permeabilized fibre bundles) is increasingly used in clinical diagnostic and basic research settings. However, estimates of the Km for ADP vary considerably (~20-300 μM) and tend to overestimate respiration at rest. Noting that PmFBs spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP-stimulated respiratory kinetics. BLEB (blebbistatin), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high Km values for ADP of >~250 and ~80 μM in red and white rat PmFBs respectively. In the absence of BLEB, PmFBs contracted and the Km for ADP decreased ~2-10-fold in a temperature-dependent manner. PmFBs were sensitive to hyperoxia (increased Km) in the absence of BLEB (contracted) at 30 °C but not 37 °C. In PmFBs from humans, contraction elicited high sensitivity to ADP (Km<100 μM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a Km for ADP of ~1560 μM, consistent with estimates of in vivo resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.
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16 MeSH Terms