Decrease In Oxidative Capacity Research Articles

Iron(III)-(1,10-Phenanthroline) Complex Can Enhance Ferrate(VI) and Ferrate(V) Oxidation of Organic Contaminants via Mediating Electron Transfer.

Recent research has primarily focused on the utilization of reductants as activators for Fe(VI) to generate high-valent iron species (Fe(IV)/Fe(V)) for the degradation of emerging organic contaminants (EOCs). However, a significant drawback of this approach arises from the reaction between reductants and ferrates, leading to a decrease in oxidation capacity. This study introduces a novel discovery that highlights the potential of the iron(III)-(1,10-phenanthroline) (Fe(III)-Phen) complex as an activator, effectively enhancing the degradation of EOCs by Fe(VI) and augmenting the overall oxidation capacity of Fe(VI). The degradation of EOCs in the Fe(VI)/Fe(III)-Phen system is facilitated through two mechanisms: a direct electron transfer (DET) process and electron shuttle action. The DET process involves the formation of a Phen-Fe(III)-Fe(VI)* complex, which exhibits a stronger oxidation ability than Fe(VI) alone and can accept electrons directly from EOCs. On the other hand, the electron shuttle process utilizes Fe(III)-Phen as a redox mediator to transfer electrons from EOCs to Fe(VI) through the Fe(IV)/Fe(III) or Fe(IV)/Fe(II)/Fe(III) cycle. Moreover, the Fe(III)-Phen complex can improve the utilization efficiency of Fe(V) by preventing its self-decay. This study's findings may present a viable option for utilizing an effective catalyst to enhance the oxidation of EOCs by Fe(VI) and Fe(V).

Adiponectin overexpression in C2C12 myocytes increases lipid oxidation and myofiber transition.

Metabolic syndrome and obesity have detrimental effects on the metabolic function of the skeletal muscle. Mounting evidence indicates that patients with those conditions may present an increased ratio of glycolytic to oxidative fibers associated with a decrease in oxidative capacity. In this regard, adiponectin, a hormone mainly secreted by adipocytes that regulates glucose and lipid metabolism, has emerged as a myokine that could play an important role in this process. We aimed to investigate whether adiponectin overexpression in skeletal muscle might be a local protective mechanism, favoring fatty acid utilization. To that end, we generated an in vitro model of myocytes with upregulated endogenous adiponectin using a lentiviral carrier. We demonstrated that the adiponectin-transduced myocytes were able to produce and secrete fully functional adiponectin complexes. Adiponectin overexpression remarkably upregulated the mRNA level of myogenic regulatory factors as well as genes implicated in lipolysis (HSL, ATGL) and cellular and mitochondrial fatty acid transport (LPL, CD36, CPT1B). This was accompanied by increased isoproterenol-induced lipolysis and β-oxidation and reduced lipogenesis, whereas insulin-stimulated glucose uptake was unaltered in transduced myocytes. Lastly, the relative expression of the more glycolytic myofibers (MyHC IIb) compared to the more oxidative ones (MyHC I) was notably reduced. Our results showed that the released adiponectin acted in an autocrine/paracrine manner, increasing lipid oxidation in myocytes and leading to a transition of myofibers from the glycolytic to the oxidative type. In conclusion, muscle adiponectin overexpression might be a way to relieve muscle diseases caused by oxidative muscle fiber deficiency.

AMP deamination is sufficient to replicate an atrophy-like metabolic phenotype in skeletal muscle

BackgroundSkeletal muscle atrophy, whether caused by chronic disease, acute critical illness, disuse or aging, is characterized by tissue-specific decrease in oxidative capacity and broad alterations in metabolism that contribute to functional decline. However, the underlying mechanisms responsible for these metabolic changes are largely unknown. One of the most highly upregulated genes in atrophic muscle is AMP deaminase 3 (AMPD3: AMP → IMP + NH3), which controls the content of intracellular adenine nucleotides (AdN; ATP + ADP + AMP). Given the central role of AdN in signaling mitochondrial gene expression and directly regulating metabolism, we hypothesized that overexpressing AMPD3 in muscle cells would be sufficient to alter their metabolic phenotype similar to that of atrophic muscle. MethodsAMPD3 and GFP (control) were overexpressed in mouse tibialis anterior (TA) muscles via plasmid electroporation and in C2C12 myotubes using adenovirus vectors. TA muscles were excised one week later, and AdN were quantified by UPLC. In myotubes, targeted measures of AdN, AMPK/PGC-1α/mitochondrial protein synthesis rates, unbiased metabolomics, and transcriptomics by RNA sequencing were measured after 24 h of AMPD3 overexpression. Media metabolites were measured as an indicator of net metabolic flux. At 48 h, the AMPK/PGC-1α/mitochondrial protein synthesis rates, and myotube respiratory function/capacity were measured. ResultsTA muscles overexpressing AMPD3 had significantly less ATP than contralateral controls (−25%). In myotubes, increasing AMPD3 expression for 24 h was sufficient to significantly decrease ATP concentrations (−16%), increase IMP, and increase efflux of IMP catabolites into the culture media, without decreasing the ATP/ADP or ATP/AMP ratios. When myotubes were treated with dinitrophenol (mitochondrial uncoupler), AMPD3 overexpression blunted decreases in ATP/ADP and ATP/AMP ratios but exacerbated AdN degradation. As such, pAMPK/AMPK, pACC/ACC, and phosphorylation of AMPK substrates, were unchanged by AMPD3 at this timepoint. AMPD3 significantly altered 191 out of 639 detected intracellular metabolites, but only 30 transcripts, none of which encoded metabolic enzymes. The most altered metabolites were those within purine nucleotide, BCAA, glycolysis, and ceramide metabolic pathways. After 48 h, AMPD3 overexpression significantly reduced pAMPK/AMPK (−24%), phosphorylation of AMPK substrates (−14%), and PGC-1α protein (−22%). Moreover, AMPD3 significantly reduced myotube mitochondrial protein synthesis rates (−55%), basal ATP synthase-dependent (−13%), and maximal uncoupled oxygen consumption (−15%). ConclusionsIncreased expression of AMPD3 significantly decreased mitochondrial protein synthesis rates and broadly altered cellular metabolites in a manner similar to that of atrophic muscle. Importantly, the changes in metabolites occurred prior to reductions in AMPK signaling, gene expression, and mitochondrial protein synthesis, suggesting metabolism is not dependent on reductions in oxidative capacity, but may be consequence of increased AMP deamination. Therefore, AMP deamination in skeletal muscle may be a mechanism that alters the metabolic phenotype of skeletal muscle during atrophy and could be a target to improve muscle function during muscle wasting.

Abstract PO-028: Investigating the contribution of CHAC1 to persistent mitochondrial respiratory function in NSCLC under cysteine deprivation

Abstract Solid tumors exhibit metabolic rewiring to enhance their energetic capacity while meeting the biosynthetic demands for rapid proliferation. Though this reprogramming supports robust tumor growth, it often imposes bottlenecks and metabolic dependencies that can be exploited clinically. Among the metabolic vulnerabilities that is of therapeutic interest is the sensitivity of many cancers to sustained deprivation of the non-essential amino acid cysteine (Cys). In certain malignant contexts, ferroptosis has been linked to mitochondrial dysfunction, where oxidative metabolism drives ROS production, the loss of mitochondrial membrane integrity and respiratory function, leading to the propagation of lipid radicals that cripple cell viability. We found that while non-small cell lung cancer (NSCLC) cells are susceptible to Cys-starvation induced ferroptosis, mitochondrial respiratory function robustly persists under prolonged Cys deprivation in these NSCLC cells. We also find that mitochondrial iron-sulfur (Fe-S) protein function (e.g. aconitase, lipoic acid synthase, and respiratory complexes I-III) critical to oxidative metabolism is unaltered by Cys deprivation despite the need for Cys-derived sulfur in the synthesis of Fe-S clusters. Under these Cys-restricted conditions, we observe an increase in the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1), a mitochondrial protein that catalyzes the degradation of the antioxidant glutathione (GSH). Because Cys is a constituent of the tripeptide antioxidant, enhanced mitochondrial GSH turnover could provide Cys for the generation of Fe-S clusters. Consistent with this, CRISPR-mediated knockout of CHAC1 diminished Fe-S protein function in Cys-starved NSCLC cells. Despite this decrease in oxidative capacity, CHAC1 knockout prolonged survival under Cys-deprivation, suggesting that intact mitochondrial function may contribute to Cys-starvation induced cell death. Enhanced GSH degradation by CHAC1 would also restrict GSH-based antioxidant capacity imposing a greater requirement for the NADPH-dependent thioredoxin system. Interestingly, we find that Cys deprivation also induces the expression of nicotinamide nucleotide transhydrogenase (NNT), a critical contributor of mitochondrial NADPH in lung cancer. Moreover, we find that the activity of the mitochondrial NADPH-producing isocitrate dehydrogenase (IDH2) is enhanced under Cys deprivation independent of a change in expression. Collectively, these data indicate a potential rewiring of mitochondrial antioxidant defenses for the maintenance of robust mitochondrial respiratory function in the absence of extracellular Cys. This ultimately may constitute a self-defeating response to nutrient stress in NSCLC, where mitochondria selfishly sustain functionality at the expense of cell viability. Citation Format: Nathan P. Ward, Gina M. DeNicola. Investigating the contribution of CHAC1 to persistent mitochondrial respiratory function in NSCLC under cysteine deprivation [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-028.

Mild hyperbaric oxygen: mechanisms and effects.

Adequate oxygen supply by exposure to mild hyperbaric oxygen at appropriately high atmospheric pressure (1266-1317hPa) and increased oxygen concentration (35-40% oxygen) has a possibility of improving the oxidative metabolism in cells and tissues without barotrauma and excessive production of reactive oxygen species. Therefore, metabolic syndrome and lifestyle-related diseases, including type 2 diabetes and hypertension, in rats were inhibited and/or improved by exposure to mild hyperbaric oxygen. It accelerated the growth-induced increase in oxidative capacity of the skeletal muscle in rats and inhibited the age-related decrease in oxidative capacity of the skeletal muscle in mice. A decrease in dopaminergic neurons in the substantia nigra of mice with Parkinson's disease was inhibited by exposure to mild hyperbaric oxygen. This review describes the beneficial effects of exposure to mild hyperbaric oxygen on some metabolic diseases and their perspectives.

Time course of denervation-induced changes in gastrocnemius muscles of adult and old rats

Denervation leads to significant muscle atrophy, but it is less clear whether 1) loss of capillaries, fibre size and oxidative capacity decline in parallel and 2) the time course of these changes differs between young and old animals. To investigate this, we denervated the left gastrocnemius muscle for 1, 2 or 4 weeks, while the right muscle served as an internal control, in rats that were 5 or 25 months old at the end of the experiment. In the fast part of the gastrocnemius muscle, almost all atrophy had occurred after two weeks (42%) of denervation. Even after 4 weeks of denervation, there was no significant reduction in the oxidative capacity of the muscle. Significant capillary loss occurred only after 4 weeks of denervation (P < 0.001) that lagged behind and was less than proportional to the decrease in fibre size. Consequently, the capillary density was elevated (P < 0.001). The time course of these morphological changes was similar in the 5- and 25-month-old rats. Comparing these data with those previously published in the soleus muscle from the same animals show that the decrease in oxidative capacity and capillary rarefaction were more pronounced and occurred earlier than in the gastrocnemius muscle, respectively. The time course of capillary loss lagged behind the decrease in fibre size, and combined with the absence of denervation-induced changes in oxidative capacity this resulted in a muscle capillary supply in excess of that expected by the metabolism and fibre size at least during the first 4 weeks after denervation.

Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques.

Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation. Ob/WSD fetuses also had reduced mitochondrial content, diminished oxidative capacity, and lower mitochondrial efficiency in muscle. The decrease in oxidative capacity and glucose metabolism was persistent in primary myotubes from Ob/WSD fetuses despite no additional lipid-induced stress. Switching obese mothers to a healthy diet prior to pregnancy did not improve fetal muscle mitochondrial function. Lastly, while maternal WSD alone led only to intermediary changes in fetal muscle metabolism, it was sufficient to increase oxidative damage and cellular stress. Our findings suggest that maternal obesity or WSD, alone or in combination, leads to programmed decreases in oxidative metabolism in offspring muscle. These alterations may have important implications for future health.

Contractile Properties of the Rat Extensor Digitorum Longus Muscle in Relation to Regional Variation in Fibre Type Composition

Muscle contractile characteristics are commonly investigated in relation to global phenotype. The extensor digitorum longus (EDL) muscle has frequently been used in physiological studies as an example of a typical fast muscle. However, the fibre type composition is not homogeneous. In the rat, the EDL contains a mixture of oxidative and glycolytic fibres, heterogeneously distributed across the muscle cross section to produce a gradient of aerobic capacity. The aim of this study was to characterize the contractile characteristics of this mixed muscle in relation to the regional variation in fibre type composition. It was hypothesized that isometric twitch characteristics and optimal frequency for power generation would not differ regionally, while the fatigability will correlate with aerobic capacity.The EDL muscle from male Wistar rats comprises four segments which insert on to phalanges 2–5; we used the medial and lateral segments, which insert on to phalanges 2 and 5, respectively. The contractile characteristics of each segment were determined under isometric conditions, in order to quantify twitch kinetics and tetanic stress. Power output of the muscle was measured at a range of cycle frequencies during cyclical contractions, using the work loop technique. The ability to sustain power was quantified using a series of repeated cyclical contractions. A range of monoclonal antibodies was used to determine fibre type composition.The two muscle segments had significantly different fibre type composition; the medial segment containing 41% Type IIb, 49% Type IIa and 10% Type I while the lateral segment contained 95% Type IIb and 5% Type IIa. The medial segment had slower twitch kinetics than the lateral segment, consistent with the presence of Type 1 fibres and lower proportion of Type 2 fibres. Isometric stress was lower in the medial segment producing 155.3 kN m−2 compared to 194.6 kN m−2 in the lateral segment; this may be related to the higher proportion of non‐contractile elements such as mitochondria in the medial segment, i.e. a lower proportion of myofibrils, compared with the lateral segment. Peak net power output and the frequency at which this was attained were similar between both muscle segments.Variation in the physiological properties of the lateral and medial segments of the rat EDL are consistent with the decrease in oxidative capacity and a decrease in the proportion of fast‐twitch fibres from medial to lateral sides. This suggests that there may be regional variation in mechanical function, with a shift from the medial segment providing work for ankle flexion at relatively low speeds, to the lateral segment increasingly fulfilling the role at higher speeds.

Fat Quality Influences the Obesogenic Effect of High Fat Diets.

High fat and/or carbohydrate intake are associated with an elevated risk for obesity and chronic diseases such as diabetes and cardiovascular diseases. The harmful effects of a high fat diet could be different, depending on dietary fat quality. In fact, high fat diets rich in unsaturated fatty acids are considered less deleterious for human health than those rich in saturated fat. In our previous studies, we have shown that rats fed a high fat diet developed obesity and exhibited a decrease in oxidative capacity and an increase in oxidative stress in liver mitochondria. To investigate whether polyunsaturated fats could attenuate the above deleterious effects of high fat diets, energy balance and body composition were assessed after two weeks in rats fed isocaloric amounts of a high-fat diet (58.2% by energy) rich either in lard or safflower/linseed oil. Hepatic functionality, plasma parameters, and oxidative status were also measured. The results show that feeding on safflower/linseed oil diet attenuates the obesogenic effect of high fat diets and ameliorates the blood lipid profile. Conversely, hepatic steatosis and mitochondrial oxidative stress appear to be negatively affected by a diet rich in unsaturated fatty acids.

Effects of microgravity on the mouse triceps brachii muscle.

In this study we investigated the effects of microgravity on the fiber properties of the mouse triceps brachii, a forelimb muscle that has no antigravity function. Mice (n = 7) were exposed to microgravity for 13 days on the space shuttle Atlantis (Space Transportation System-135). The fiber cross-sectional area (CSA) and succinate dehydrogenase (SDH) staining intensity of the triceps brachii muscle were compared with those of controls (n = 7). SDH activity in this muscle was also estimated. Microgravity did not affect the body weight, muscle weight, or fiber CSA, but there was reduced SDH staining intensity of all types of fibers, irrespective of the muscle region (P < 0.05). Microgravity also reduced muscle SDH activity (P < 0.05). Short-term exposure to microgravity induced a decrease in oxidative capacity, but not atrophy, in the triceps brachii muscle of mice.

Abstracts

Muscle unloading, as encountered during space flight and disuse, induces skeletal muscle atrophy and weakness, switch of fibre types and loss of capillaries. Less attention has been given to disuse-induced changes in oxidative capacity, which may affect endurance. Here we investigated the impact of 21 days, 60 head-down bed rest on muscle fibre size, fibre type composition, capillarisation and muscle oxidative capacity and the efficacy of milk-based proteins (whey protein) to counteract disuse-induced muscle changes. Muscle biopsies were taken from the soleus (SOL) and vastus lateralis (VL)muscles before and after bed rest from10 healthy men (aged 31 ± 6 years). Subjects were assigned to two groups and studied twice in two follow-up campaigns, in once receiving whey protein and once receiving a standardized isocaloric diet. Fibre types and capillaries were identified by immunohistochemical staining of muscle section with anti-myosin type1 and lectin. Analysis was done with the method of capillary domains.Oxidative capacity of individual fibres was determined as the optical density (OD) at 660 nm of succinate dehydrogenase (SDH) stained histological sections. The fibre cross-sectional area times the SDH-OD of that fibre (integrated SDH) was index of maximal oxygen consumption of that fibre(VO2max). Statistical analysis was done by repeated measures ANOVA. Bed rest did not induce significant changes infibre type composition, fibre size or capillarisation, but decreased SDH activity (p\0.001) and fibre VO2max (p\0.01) in both muscles. Whey protein partially counteracted the decrease in oxidative capacity. Our results suggest that decrements in oxidative capacity may be an early hallmark of disuse-induced muscle adaptations and occurs even in the absence of significant fibre atrophy and capillary rarefaction. The Whey diet attenuated these effects and may thus be an effective supplement to sustain oxidative capacity during space flight and long-term bed rest.

Alterations in proton leak, oxidative status and uncoupling protein 3 content in skeletal muscle subsarcolemmal and intermyofibrillar mitochondria in old rats.

BackgroundWe considered of interest to evaluate how aging affects mitochondrial function in skeletal muscle.MethodsWe measured mitochondrial oxidative capacity and proton leak, together with lipid oxidative damage, superoxide dismutase specific activity and uncoupling protein 3 content, in subsarcolemmal and intermyofibrillar mitochondria from adult (six months) and old (two years) rats. Body composition, resting metabolic rate and plasma non esterified fatty acid levels were also assessed.ResultsOld rats displayed significantly higher body energy and lipids, while body proteins were significantly lower, compared to adult rats. In addition, plasma non esterified fatty acid levels were significantly higher, while resting metabolic rates were found to be significantly lower, in old rats compared to adult ones. Significantly lower oxidative capacities in whole tissue homogenates and in intermyofibrillar and subsarcolemmal mitochondria were found in old rats compared to adult ones. Subsarcolemmal and intermyofibrillar mitochondria from old rats exhibited a significantly lower proton leak rate, while oxidative damage was found to be significantly higher only in subsarcolemmal mitochondria. Mitochondrial superoxide dismutase specific activity was not significantly affected in old rats, while significantly higher content of uncoupling protein 3 was found in both mitochondrial populations from old rats compared to adult ones, although the magnitude of the increase was lower in subsarcolemmal than in intermyofibrillar mitochondria.ConclusionsThe decrease in oxidative capacity and proton leak in intermyofibrillar and subsarcolemmal mitochondria could induce a decline in energy expenditure and thus contribute to the reduced resting metabolic rate found in old rats, while oxidative damage is present only in subsarcolemmal mitochondria.

Effects of sustained hypoxia on sternohyoid and diaphragm muscle during development

Sustained hypoxia is a dominant feature of respiratory disease. Despite the clinical significance, the effects of sustained hypoxia on the form and function of respiratory muscle during development are relatively underexplored. Wistar rats were exposed to 1 week of sustained hypoxia (ambient pressure 450 mmHg) or normoxia at various time points during development. Sternohyoid and diaphragm muscle contractile and endurance properties were assessed in vitro. Muscle succinate dehydrogenase and myosin heavy chain composition were determined. The role of reactive oxygen species in hypoxia-induced muscle remodelling was assessed. Sustained hypoxia increased sternohyoid muscle force and fatigue in early but not late development, effects that persisted after return to normoxia. Hypoxia-induced sternohyoid muscle fatigue was not attributable to fibre type transitions or to a decrease in oxidative capacity. Chronic supplementation with the superoxide scavenger tempol did not prevent hypoxia-induced sternohyoid muscle fatigue, suggesting that mechanisms unrelated to oxidative stress underpin hypoxia-induced maladaptation in sternohyoid muscle. Sustained hypoxia had no effect on diaphragm muscle fatigue. We conclude that there are critical windows during development for hypoxia-induced airway dilator muscle maladaptation. Sustained hypoxia-induced impairment of upper airway muscle endurance may persist into later life. Upper airway muscle dysfunction could have deleterious consequences for the control of pharyngeal airway calibre in vivo.

Active halogen compounds and proteinaceous material: loss of activity of topical anti-infectives by halogen consumption

The activity of oxidants, such as halogens and active halogen compounds, decreases generally in the presence of proteinaceous material. A quantification of consumption effects was performed to judge the suitability of different representatives as antiseptics and their compatibility with pharmaceutical additives. An iodometric approach served to assess the temporal loss of oxidation capacity in the presence of peptone and fetal calf serum (FCS). The tested agents comprised active halogen compounds, well-known and in particular novel chloramine-based agents indicated for the topical treatment of infections. The decrease in oxidation capacity was higher in the presence of FCS than of peptone and correlated with the reactivity of the oxidants in both cases. The highest consumption rates were for active bromine compounds followed by hypochlorous acid and heterocyclic chlorimides, such as dichloro-isocyanuric acid, while N-chlorotaurine and related amine-based analogues were least consumed. The pH dependence was only remarkable for chloramine T. The observed consumption effects are the result of the differing oxidizing (chlorinating) potencies. Since consumption and irritation are founded on the very same reactions, representatives with low reactivity (N-chloro amino acids) are regarded as more tolerable and retain more oxidative capacity, which provides a more sustained antimicrobial activity.

Impaired mitochondrial respiration and decreased fatigue resistance followed by severe muscle weakness in skeletal muscle of mitochondrial DNA mutator mice

Mitochondrial dysfunction can drastically impair muscle function, with weakness and exercise intolerance as key symptoms. Here we examine the time course of development of muscle dysfunction in a mouse model of premature ageing induced by defective proofreading function of mitochondrial DNA (mtDNA) polymerase (mtDNA mutator mouse). Isolated fast-twitch muscles and single muscle fibres from young (3-5 months) and end-stage (11 months) mtDNA mutator mice were compared to age-matched control mice. Force and free myoplasmic [Ca(2+)] ([Ca(2+)](i)) were measured under resting conditions and during fatigue induced by repeated tetani. Muscles of young mtDNA mutator mice displayed no weakness in the rested state, but had lower force and [Ca(2+)](i) than control mice during induction of fatigue. Muscles of young mtDNA mutator mice showed decreased activities of citrate synthase and β-hydroxyacyl-coenzyme A dehydrogenase, reduced expression of cytochrome c oxidase, and decreased expression of triggers of mitochondrial biogenesis (PGC-1α, PPARα, AMPK). Muscles from end-stage mtDNA mutator mice showed weakness under resting conditions with markedly decreased tetanic [Ca(2+)](i), force per cross-sectional area and protein expression of the sarcoplasmic reticulum Ca(2+) pump (SERCA1). In conclusion, fast-twitch muscles of prematurely ageing mtDNA mutator mice display a sequence of deleterious mitochondrial-to-nucleus signalling with an initial decrease in oxidative capacity, which was not counteracted by activation of signalling to increase mitochondrial biogenesis. This was followed by severe muscle weakness in the end stage. These results have implication for normal ageing and suggest that decreased mitochondrial oxidative capacity due to a sedentary lifestyle may predispose towards muscle weakness developing later in life.

Commentaries on Viewpoint: Do oxidative and anaerobic energy production in exercising muscle change throughout growth and maturation?

Commentaries on Viewpoint: Do oxidative and anaerobic energy production in exercising muscle change throughout growth and maturation?

Bio-energetic impairment in human calf muscle in thyroid disorders: a 31P MRS study

Mitochondrial metabolism particularly oxidative phosphorylation is greatly influenced by thyroid hormones. Earlier studies have described neuromuscular symptoms as well as impaired muscle metabolism in hypothyroid and hyperthyroid patients. In this study, we intend to look in to the muscle bioenergetics including phosphocreatine recovery kinetics based oxidative metabolism in thyroid dysfunction using in vivo (31)P nuclear magnetic resonance spectroscopy (MRS). (31)P MRS was carried out at resting state on 32 hypothyroid, 10 hyperthyroid patients and 25 control subjects. Nine out of 32 hypothyroid patients and 17 out of 25 control subjects under went exercise protocol for oxidative metabolism study and performed plantar flexion exercise while lying supine in 1.5 T magnetic resonance scanner using custom built exercise device. MRS measurements of inorganic phosphate (Pi), phosphocreatine (PCr), phosphodiesters (PDE) and adenosine triphosphate (ATP) of the calf muscle were acquired during rest, exercise and recovery phase. PCr recovery rate constant (k(PCr)) and oxidative capacity were calculated by monoexponential fit of PCr versus time (t) at the beginning of recovery. During resting condition in hypothyroid patients, PCr/Pi ratio was reduced whereas PDE/ATP and Pi/ATP were increased. However, in case of hyperthyroidism, an increased PCr/Pi ratio and reduced PDE/ATP and Pi/ATP were observed. The results confirmed differential energy status of the muscle due to increased or decreased levels of thyroid hormone. Our results also demonstrate reduced oxidative metabolism in hypothyroid patients based on PCr recovery kinetics. PCr recovery kinetics study after exercise revealed decreased PCr recovery rate constant (k(PCr)) in hypothyroid patients compared to controls that resulted in decrease in oxidative capacity of muscle by 50% in hypothyroids. These findings are consistent with a defect of high energy phosphate mitochondrial metabolism in thyroid dysfunction.

Hyperbaric Oxygen Exposure Reduces Age-Related Decrease in Oxidative Capacity of the Tibialis Anterior Muscle in Mice

The effects of exposure to hyperbaric oxygen on the oxidative capacity of the skeletal muscles in mice at different ages were investigated. We exposed 5-, 34-, 55-, and 88-week-old mice to 36% oxygen at 950 mmHg for 6 hours per day for 2 weeks. The activities of succinate dehydrogenase (SDH), which is a mitochondrial marker enzyme, of the tibialis anterior muscle in hyperbaric mice were compared with those in age-matched mice under normobaric conditions (21% oxygen at 760 mmHg). Furthermore, the SDH activities of type IIA and type IIB fibers in the muscle were determined using quantitative histochemical analysis. The SDH activity of the muscle in normobaric mice decreased with age. Similar results were observed in both type IIA and type IIB fibers in the muscle. The decrease in the SDH activity of the muscle was reduced in hyperbaric mice at 57 and 90 weeks. The decreased SDH activities of type IIA and type IIB fibers were reduced in hyperbaric mice at 90 weeks and at 57 and 90 weeks, respectively. We conclude that exposure to hyperbaric oxygen used in this study reduces the age-related decrease in the oxidative capacity of skeletal muscles.

Effects Of Old Age And Physical Activity On Oxidative Capacity In Human Skeletal Muscle

Studies of the effects of old age on muscle oxidative capacity have led to contradictory results. These discrepancies may be due in part to muscle-specific differences in the effects of altered physical activity patterns in the elderly. PURPOSE: To determine if training status has differential effects on oxidative capacity in vivo in two lower limb muscles, tibialis anterior (TA) and vastus lateralis (VL), in young and older men. METHODS: We used phosphorus magnetic resonance spectroscopy (MRS) to measure muscle oxidative capacity non-invasively in young (n=8, 25±4 yrs, mean±SD) and older (n=8, 69±4) healthy, untrained men; and young (n=7, 28±3) and older (n=3, 71±8) male runners. In separate trials, subjects performed a 16-s and a 24-s maximal voluntary isometric contraction of the TA and VL, respectively, while phosphocreatine (PCr) was measured using a 4 tesla MRS system. Resynthesis of [PCr] followed a mono-exponential time course with a rate constant, kPCr, that is attributable to ATP synthesis from oxidative phosphorylation. A three-way (group, muscle, age) ANOVA was applied. RESULTS: There was a main effect of group such that kPCr was higher in trained than untrained men (p<0.001). There was also an age-by-muscle interaction such that kPCr was greater in young compared to older men in VL (p=0.009), but not in TA, regardless of training status.TableCONCLUSION: The decrease in oxidative capacity observed in the VL but not the TA of both older groups provides evidence of a muscle-specific effect of aging that is independent of training status. These results also confirm greater muscle oxidative capacity in vivo in two muscles of the lower limb in trained compared to untrained men. NIH/NIA R01 AG21094, K02 023582; ACSM Student Grant (RGL)

Age-related differences in skeletal muscle insulin signaling: the role of stress kinases and heat shock proteins

Aging is associated with an increase in insulin resistance in skeletal muscle, yet the underlying mechanism is not well established. We hypothesize that with aging, a chronic increase in stress kinase activation, coupled with a decrease in oxidative capacity, leads to insulin resistance in skeletal muscle. In aged (24 mo old) and young (3 mo old) Fischer 344 rats, 2-deoxyglucose uptake and insulin signaling [as measured by phosphorylation of insulin receptor substrate-1 (IRS-1), Akt (protein kinase B), and Akt substrate of 160 kDa (AS160)] decreased significantly with age. Activation of, c-Jun NH(2)-terminal kinase (JNK), glycogen serine kinase-3beta (GSK-3beta), and degradation of IkappaBalpha by the upstream inhibitor of kappa B kinase (IKKbeta), as measured by Western blot analysis, were increased with age in both soleus and epitrochlearis (Epi) muscles. However, much higher activation of these kinases in Epi muscles from young rats compared with soleus results in a greater effect of these kinases on insulin signaling in fast-twitch muscle with age. Heat shock protein (HSP) 72 expression and phosphorylation of HSP25 were higher in soleus compared with Epi muscles, and both parameters decreased with age. Age and fiber type differences in cytochrome oxidase activity are consistent with observed changes in HSP expression and activation. Our results demonstrate a significant difference in the ability of slow-twitch and fast-twitch muscles to respond to insulin and regulate glucose with age. A greater constitutive HSP expression and lower stress kinase activation may account for the ability of slow-twitch muscles to preserve the capacity to respond to insulin and maintain glucose homeostasis with age.