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Hunter 2019 J Appl Physiol (1985) + (Aerobic capacity is negatively related to … Aerobic capacity is negatively related to locomotion economy. The purpose of the paper is to determine what effects aerobic exercise training has on the relationship between net cycling oxygen uptake (inverse of economy) and aerobic capacity (VO2peak) as well as what role mitochondrial coupled and uncoupled respiration may play in whole body aerobic capacity and cycling economy.Cycling net oxygen uptake and VO2peak were evaluated on 52 subjects prior to exercise training (baseline) and 31 subjects after 8-16 weeks of aerobic training. Muscle tissue was collected from 25 subjects at baseline and 15 post training. Mitochondrial respiration assays were performed using High Resolution Respirometry.Pre (r=0.34, p<0.05) and post exercise training (r=0.62, p<0.01) VO2peak and cycling net oxygen uptake were related. In addition, uncoupled and coupled fat respiration were related both baseline (r=0.89, p<0.01) and post training (r=0.89, p<01). Post training coupled (r=0.74, p<0.01) and uncoupled carbohydrate respiration (r=0.52, p<05) were related to cycle net oxygen uptake. In addition, correlations between changes in VO2peak and changes in cycle net oxygen uptake persist after training, even after adjusting for changes in RQ (an index of fat oxidation).These results suggest that the negative relationship between locomotion economy and aerobic capacity is increased following exercise training. In addition, it is proposed that at least one of the primary factors influencing this relationship has its foundation within the mitochondria. Strong relationships between coupled and uncoupled respiration appear to be contributing factors for this relationship.tionships between coupled and uncoupled respiration appear to be contributing factors for this relationship.)
Hunter 2019 J Appl Physiol + (Aerobic capacity is negatively related to … Aerobic capacity is negatively related to locomotion economy. The purpose of this paper is to determine what effect aerobic exercise training has on the relationship between net cycling oxygen uptake (inverse of economy) and aerobic capacity [peak oxygen uptake (V̇o2peak)], as well as what role mitochondrial coupled and uncoupled respiration may play in whole body aerobic capacity and cycling economy. Cycling net oxygen uptake and ''V̇''o2peak were evaluated on 31 premenopausal women before exercise training (baseline) and after 8-16 wk of aerobic training. Muscle tissue was collected from 15 subjects at baseline and post-training. Mitochondrial respiration assays were performed using high-resolution respirometry. Pre- (''r'' = 0.46, ''P'' < 0.01) and postexercise training (''r'' = 0.62, ''P'' < 0.01) ''V̇''o2peak and cycling net oxygen uptake were related. In addition, uncoupled and coupled fat respiration were related both at baseline (''r'' = 0.62, ''P'' < 0.01) and post-training (''r'' = 0.89, ''P'' < 01). Post-training coupled (''r'' = 0.74, ''P'' < 0.01) and uncoupled carbohydrate respiration (''r'' = 0.52, ''P'' < 05) were related to cycle net oxygen uptake. In addition, correlations between ''V̇''o2peak and cycle net oxygen uptake persist both at baseline and after training, even after adjusting for submaximal cycle respiratory quotient (an index of fat oxidation). These results suggest that the negative relationship between locomotion economy and aerobic capacity is increased following exercise training. In addition, it is proposed that at least one of the primary factors influencing this relationship has its foundation within the mitochondria. Strong relationships between coupled and uncoupled respiration appear to be contributing factors for this relationship.NEW & NOTEWORTHY: The negative relationship between cycle economy and aerobic capacity is increased following exercise training. The strong relationship between coupled and uncoupled respiration, especially after training, appears to be contributing to this negative relationship between aerobic capacity and cycling economy, suggesting that mitochondrial economy is not increased following aerobic exercise training. These results are suggestive that training programs designed to improve locomotion economy should focus on changing biomechanics.mprove locomotion economy should focus on changing biomechanics.)
Dawson 2022 FASEB J + (Aerobic energy demands have led to the evo … Aerobic energy demands have led to the evolution of complex mitochondrial reticula in highly oxidative muscles, but the extent to which metabolic challenges can be met with adaptive changes in physiology of specific mitochondrial fractions remains unresolved. We examined mitochondrial mechanisms supporting adaptive increases in aerobic performance in deer mice (''Peromyscus maniculatus'') adapted to the hypoxic environment at high altitude. High-altitude and low-altitude mice were born and raised in captivity, and exposed as adults to normoxia or hypobaric hypoxia (12 kPa O2 for 6-8 weeks). Subsarcolemmal and intermyofibrillar mitochondria were isolated from the gastrocnemius, and a comprehensive substrate titration protocol was used to examine mitochondrial physiology and O2 kinetics by high-resolution respirometry and fluorometry. High-altitude mice had greater yield, respiratory capacity for oxidative phosphorylation, and O2 affinity (lower P50 ) of subsarcolemmal mitochondria compared to low-altitude mice across environments, but there were no species difference in these traits in intermyofibrillar mitochondria. High-altitude mice also had greater capacities of complex II relative to complexes I + II and higher succinate dehydrogenase activities in both mitochondrial fractions. Exposure to chronic hypoxia reduced reactive oxygen species (ROS) emission in high-altitude mice but not in low-altitude mice. Our findings suggest that functional changes in subsarcolemmal mitochondria contribute to improving aerobic performance in hypoxia in high-altitude deer mice. Therefore, physiological variation in specific mitochondrial fractions can help overcome the metabolic challenges of life at high altitude.fractions can help overcome the metabolic challenges of life at high altitude.)
Gnaiger 2005 Abstract MiP2005 + (Aerobic exercise and several aspects of li … Aerobic exercise and several aspects of life style influence mitochondrial respiratory function in human muscle, in addition to effects of age, gender and genetic background. In the present study, a significant part of the variability in respiration of human mitochondria [1] was explained by analysis of readily accessible background information on 25 healthy human subjects (19 males and 6 females; 22 to 46 years). Based on a novel multi-substrate/inhibitor protocol, this approach advances the functional analysis in mitochondrial physiology and pathology.A protocol for high-resolution respirometry (with two or three Oroboros Oxygraph-2k operated in parallel) was designed for quantification of mitochondrial respiratory capacities in permeabilized muscle fibers obtained from small needle biopsies (2 to 6 mg per run; 2 or 4 runs per subject). Cell membranes were selectively permeabilized [2], and lack of respiratory stimulation by cytochrome c indicated an intact outer mitochondrial membrane (Fig. 1). Measurements were performed at 30 °C in the range of 20 to 50 kPa oxygen pressure (210 to 530 µM), to avoid oxygen limitation [3]. In this range, autoxidation of ascorbate and TMPD was a linear function of oxygen, which was applied for correction of chemical background oxygen flux.ADP-stimulated respiration with malate+octanoylcarnitine (state OM3) was 46 % compared to further addition of glutamate (state GM3). An additive effect was exerted by parallel complex I+II electron input (the GS3/GM3 ratio was 1.6), since respiration with succinate/rotenone (S3) was only 1.1 times the state GM3 (Fig. 1). In a variation of this protocol, FCCP was titrated upon state GS3, yielding a further 44 % increase (and a corresponding GSu/GM3 ratio of 2.4). State GS3, therefore, reflects the capacity of the phosphorylation system, in agreement with results on isolated mitochondria [4]. The coupled state GS3 represents the physiologically relevant upper limit of respiration, providing parallel complex I and II input in accordance with an operational TCA cycle. The physiological excess capactiy of COX, expressed as the COX/GM3 ratio was 2.7, whereas the COX/GS3 ratio was 1.4. Respiratory adenylate control ratios were identical with octanoylcarnitie (OM3/OM2) and succinate (S3/S4o).State GS3 declined significantly as a function of body mass index (BMI; body weight/hight2) in the 19 males, which explained ~60 % of total variability. BMI was independent of age, as was the GS3 respiratory capacity. Fatty acid oxidation capacity (state OM3), however, declined significantly with age (males and females combined), thus extending a study on isolated mitochondria [1] to a surprisingly narrow range of ages. Consideration of BMI and age, therefore, improves the diagnostic resolution of functional mitochondrial respiratory analyses.tional mitochondrial respiratory analyses.)
Suhane 2013 Bio Open + (Aerobic glycolysis in transformed cells is … Aerobic glycolysis in transformed cells is an unique metabolic phenotype characterized by a hyperactivated glycolytic pathway even in the presence of oxygen. It is not clear if the onset of aerobic glycolysis is regulated by mitochondrial dysfunction and, if so, what the metabolic windows of opportunity available to control this metabolic switch (mitochondrial to glycolytic) landscape are in transformed cells. Here we report a genetically-defined model system based on the gene-silencing of a mitochondrial complex I subunit, NDUFS3, where we demonstrate the onset of metabolic switch in isogenic human embryonic kidney cells by differential expression of NDUFS3. By means of extensive metabolic characterization, we demonstrate that NDUFS3 gene silencing systematically introduces mitochondrial dysfunction thereby leading to the onset of aerobic glycolysis in a manner dependent on NDUFS3 protein levels. Furthermore, we show that the sustained imbalance in free radical dynamics is a necessary condition to sustain the observed metabolic switch in cell lines with the most severe NDUFS3 suppression. Together, our data reveal a novel role for mitochondrial complex I subunit NDUFS3 in regulating the degree of mitochondrial dysfunction in living cells, thereby setting a “metabolic threshold” for the observation of aerobic glycolysis phenotype within the confines of mitochondrial dysfunction.the confines of mitochondrial dysfunction.)
Jia 2018 Cells + (Aerobic glycolysis, also referred to as th … Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective.y in principle can be made more effective.)
Saura 2022 Proc Natl Acad Sci U S A + (Aerobic life is powered by membrane-bound … Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme ''a'', leads to dissociation of an arginine (Arg438)-heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å-1 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, "chemical," proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.fields generally control enzyme catalysis.)
Thoral 2021 Biol Lett + (Aerobic metabolism of aquatic ectotherms i … Aerobic metabolism of aquatic ectotherms is highly sensitive to fluctuating climates. Many mitochondrial traits exhibit phenotypic plasticity in response to acute variations in temperature and oxygen availability. These responses are critical for understanding the effects of environmental variations on aquatic ectotherms' performance. Using the European seabass, ''Dicentrarchus labrax'', we determined the effects of acute warming and deoxygenation ''in vitro'' on mitochondrial respiratory capacities and mitochondrial efficiency to produce ATP (ATP/O ratio). We show that acute warming reduced ATP/O ratio but deoxygenation marginally raised ATP/O ratio, leading to a compensatory effect of low oxygen availability on mitochondrial ATP/O ratio at high temperature. The acute effect of warming and deoxygenation on mitochondrial efficiency might be related to the leak of protons across the mitochondrial inner membrane, as the mitochondrial respiration required to counteract the proton leak increased with warming and decreased with deoxygenation. Our study underlines the importance of integrating the combined effects of temperature and oxygen availability on mitochondrial metabolism. Predictions on decline in performance of aquatic ectotherms owing to climate change may not be accurate, since these predictions typically look at respiratory capacity and ignore efficiency of ATP production.y and ignore efficiency of ATP production.)
Wone 2013 Comp Biochem Physiol A Mol Integr Physiol + (Aerobic metabolism of vertebrates is linke … Aerobic metabolism of vertebrates is linked to membrane fatty acid (FA) composition. Although the membrane pacemaker hypothesis posits that desaturation of FAs accounts for variation in resting or basal metabolic rate (BMR), little is known about the FA profiles that underpin variation in maximal metabolic rate (MMR). We examined membrane FA composition of liver and skeletal muscle in mice after seven generations of selection for increased MMR. In both liver and skeletal muscle, unsaturation index did not differ between control and high-MMR mice. We also examined membrane FA composition at the individual-level of variation. In liver, 18:0, 20:3 n-6, 20:4 n-6, and 22:6 n-3 FAs were significant predictors of MMR. In gastrocnemius muscle, 18:2 n-6, 20:4 n-6, and 22:6 n-3 FAs were significant predictors of MMR. In addition, muscle 16:1 n-7, 18:1 n-9, and 22:5 n-3 FAs were significant predictors of BMR, whereas no liver FAs were significant predictors of BMR. Our findings indicate that (i) individual variation in MMR and BMR appears to be linked to membrane FA composition in the skeletal muscle and liver, and (ii) FAs that differ between selected and control lines are involved in pathways that can affect MMR or BMR.ed in pathways that can affect MMR or BMR.)
Aragones 2009 Cell Metab + (Aerobic organisms developed mechanisms to … Aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen (O(2)). Recent studies reveal that O(2) sensors, belonging to the novel class of 2-oxoglutarate dependent iron(ii)-dioxygenases, have more important roles in metabolism than anticipated. Here, we provide a "metabolo-centric" overview of the role of the PHD/FIH members of this family in metabolism, in particular on how they regulate O(2) supply and consumption, energy compensation and conservation, O(2) conformance and hypoxia tolerance, redox and pH homeostasis, and other vital metabolic processes with implications in health and disease. These insights may offer novel opportunities for the treatment of ischemic diseases.es for the treatment of ischemic diseases.)
Pena 2020 Int J Chronic Dis + (Aerobic training (AT) can support brain he … Aerobic training (AT) can support brain health in Alzheimer’s disease (AD); however, the role of resistance training (RT) in AD is not well established. Aside from direct effects on the brain, exercise may also regulate brain function through secretion of muscle-derived myokines. Aims. This study examined the effects of AT and RT on hippocampal BDNF and IGF-1 signaling, β-amyloid expression, and myokine cathepsin B in the triple transgenic (3xTg-AD) model of AD. 3xTg-AD mice were assigned to one of the following groups: sedentary (Tg), aerobic trained (Tg+AT, 9 wks treadmill running), or resistance trained (Tg+RT, 9 wks weighted ladder climbing) (''N''=10/group). Rotarod latency and strength were assessed pre- and posttraining. Hippocampus and skeletal muscle were collected after training and analyzed by high-resolution respirometry, ELISA, and immunoblotting. Tg+RT showed greater grip strength than Tg and Tg+AT at posttraining (''p''<0.01). Only Tg+AT improved rotarod peak latency (''p''<0.01). Hippocampal IGF-1 concentration was ~15 % greater in Tg+AT and Tg+RT compared to Tg (''p''<0.05); however, downstream signals of p-IGF-1R, p-Akt, p-MAPK, and p-GSK3β were not altered. Cathepsin B, hippocampal p-CREB and BDNF, and hippocampal mitochondrial respiration were not affected by AT or RT. β-Amyloid was ~30 % lower in Tg+RT compared to Tg (''p''<0.05). This data suggests that regular resistance training reduces β-amyloid in the hippocampus concurrent with increased concentrations of IGF-1. Both types of training offered distinct benefits, either by improving physical function or by modifying signals in the hippocampus. Therefore, inclusion of both training modalities may address central defects, as well as peripheral comorbidities in AD.al defects, as well as peripheral comorbidities in AD.)
Hansen 2022 Free Radic Biol Med + (Aerobic training can improve vascular endo … Aerobic training can improve vascular endothelial function ''in-vivo''. The aim of this study was to elucidate the mechanisms underlying this improvement in isolated human microvascular endothelial cells. Sedentary males, aged 57 ± 6 years completed 8 weeks of intense aerobic training. Resting muscle biopsies were obtained from the thigh muscle and used for isolation of endothelial cells (pre n = 23, post n = 16). The cells were analyzed for mitochondrial respiration, H2O2 emission, glycolysis, protein levels of antioxidants, NADPH oxidase, endothelial nitric oxide (NO) synthase and prostacyclin synthase (PGI2S). ''In-vivo'' microvascular function, assessed by acetylcholine infusion and arterial blood pressure were also determined. Endothelial mitochondrial respiration and H2O2 formation were similar before and after training whereas the expression of superoxide dismutase and the expression of glutathione peroxidase were 2.4-fold (p = 0.012) and 2.3-fold (p = 0.006) higher, respectively, after training. ''In-vivo'' microvascular function was increased by 1.4-fold (p = 0.036) in parallel with a 2.1-fold increase in endothelial PGI2S expression (p = 0.041). Endothelial cell glycolysis was reduced after training, as indicated by a 65% lower basal production of lactate (p = 0.003) and a 30% lower expression of phosphofructokinase (p = 0.011). Subdivision of the participants according to blood pressure at base-line (n = 23), revealed a 2-fold higher (p = 0.049) rate of H2O2 production in endothelial cells from hypertensive participants. Our data show that exercise training increases skeletal muscle microvascular endothelial cell metabolism, antioxidant capacity and the capacity to form prostacyclin. Moreover, elevated blood pressure is associated with increased endothelial mitochondrial ROS formation.the capacity to form prostacyclin. Moreover, elevated blood pressure is associated with increased endothelial mitochondrial ROS formation.)
DeLany 2014 J Clin Endocrinol Metab + (African-American women (AAW) have an incre … African-American women (AAW) have an increased risk of developing type 2 diabetes compared to Caucasian women (CW). Lower insulin sensitivity has been reported in AAW, but the reasons for this racial difference and the contributions of liver versus skeletal muscle are incompletely understood.We tested the hypothesis that young, non-obese AAW manifest lower insulin sensitivity specific to skeletal muscle, not liver, and is accompanied by lower skeletal muscle mitochondrial oxidative capacity. Participants and Main Outcome Measures: Twenty-two non-obese (BMI 22.7±3.1 kg/m2) AAW and twenty-two matched CW (BMI 22.7±3.1 kg/m2) underwent characterization of body composition, objectively-assessed habitual physical activity, and insulin sensitivity with euglycemic clamps and stable-isotope tracers. Skeletal muscle biopsies were performed for lipid content, fiber-typing, and mitochondrial measurements. Peripheral insulin sensitivity was 26% lower in AAW (''p''<0.01), but hepatic insulin sensitivity was similar between groups. Physical activity levels were similar between groups. Lower insulin sensitivity in AAW was not explained by total or central adiposity. Skeletal muscle triglyceride content was similar but mitochondrial content was lower in AAW. Mitochondrial respiration was 24% lower in AAW and correlated with skeletal muscle insulin sensitivity (''r''=0.33, ''p''<0.05).When compared to CW, AAW have similar hepatic insulin sensitivity, but a muscle phenotype characterized by both lower insulin sensitivity and lower mitochondrial oxidative capacity. These observations occur in the absence of obesity and are not explained by physical activity. The only factor associated with lower insulin sensitivity in AAW was mitochondrial oxidative capacity. Because exercise training improves both mitochondrial capacity and insulin sensitivity, we suggest that it may be of particular benefit as a strategy for diabetes prevention in AAW.y be of particular benefit as a strategy for diabetes prevention in AAW.)
Brooks 2022 J Physiol + (After a century, it's time to turn the pag … After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology. major importance in 21st century biology.)
Ornelas 2017 Cancer Metastasis Rev + (After more than a century, aspirin remains … After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.y a role in its chemopreventive mechanism.)
Sumbalova 2022 Abstract Bioblast + (After overcoming COVID-19, some people dev … After overcoming COVID-19, some people develop a variety of mid- and long-term effects like fatigue, breathlessness, cognitive dysfunction as part of post COVID-19 condition. These symptoms might persist from the initial illness or develop after the recovery. Spa rehabilitation is recommended for patients with post COVID-19 syndrome. In our previous study deficit of CI-linked mitochondrial function and reduced endogenous coenzyme Q10 (CoQ10) concentration was found in platelets of non-hospitalized, non-vaccinated patients 3 – 6 weeks after acute COVID-19 [1].In this project we studied effects of mountain spa rehabilitation (MR) and MR combined with ubiquinol (reduced form of CoQ10) supplementation (MRQ) on pulmonary function, clinical and psychological symptoms, endogenous CoQ10 levels, and platelet mitochondrial bioenergetics of patients with post COVID-19 syndrome.In total, 36 patients with post COVID-19 syndrome and 15 healthy volunteers (control group) were included in the study. The patients acomplished mountain spa rehabilitation in Sanatorium of Dr. Guhr in Tatranská Polianka, High Tatras, Slovakia with individual therapeutic program including special respiratory physiotherapy procedures, mental well-being, nutrition counseling and adequate exercise therapy. Fourteen patients were on mountain spa rehabilitation (MR) lasting 16 – 18 days and 22 patients were on MR with simultaneous supplementation with ubiquinol (2x100 mg/day) lasting 16 – 18 days and on ubiquinol supplementation for next 12 – 14 days after leaving the spa. Pulmonary function by 6-minute walking test (6MWT), exercise dyspnea by Borg scale (BS), oxygen saturation (SpO2) and clinical symptoms by questionnaire were evaluated before and after 16 – 18 days of MR. Platelet bioenergetics by high-resolution respirometry, plasma TBARS concentration, and CoQ10 concentration in blood, plasma and platelets were evaluated before (MR1 and MRQ1 groups) and after MR (MR2 and MRQ2 groups), and additionally in 8 patients with CoQ10 supplementation 12 – 14 days after MR (MRQ3 group).Platelet mitochondrial Complex I (CI)-linked oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity was markedly reduced in patients with post COVID-19 syndrome vs the control group (Fig. 1). After 16 – 18 days of MR these parameters improved in both groups vs before MR. The improvement in the group of patients supplemented with ubiquinol was higher than in the non-supplemented group. CI-linked OXPHOS and ET capacity increased further after additional 12 – 14 days of CoQ10 supplementation at home (MRQ3 group).The CoQ10 concentration markedly raised after 16 – 18 days of supplementation with ubiquinol in platelets (+60%, p <0.0001), blood (+185%, p<0.0001), and plasma (+232%, p<0.0001) reflecting high bioavailability of supplemented CoQ10. The increase of platelet mitochondrial CI-linked OXPHOS and ET capacity correlated with the increase of CoQ10 in platelets and there was a trend to positive correlation between the improvement of pulmonary function and the increase of CoQ10 in platelets.These data show significant role of supplemented ubiquinol in acceleration of mitochondrial health regeneration in patients with post COVID-19 syndrome. Mountain spa rehabilitation with coenzyme Q10 supplementation could be recommended to the patients with post COVID-19 syndrome.# Sumbalová Z, Kucharská J, Palacka P, Rausová Z, Langsjoen P, Langsjoen AM, Gvozdjáková A (2022) Platelet mitochondrial function and endogenous coenzyme Q10 levels are reduced in patients after COVID-19. https://doi.org/10.4149/BLL_2022_002# [[SUIT-001 O2 ce-pce D004]]4]] )
Vaupel MiP2010 + (After several decades, the Pasteur-, Crabt … After several decades, the Pasteur-, Crabtree- and [[Warburg effect]]s have experienced a renaissance in current research. The interaction between [[glycolysis]] (i.e., the direct breakdown of glucose to lactate/lactic acid) and mitochondrial [[oxidative phosphorylation]] (i.e., glucose oxidation) was first described by Pasteur in 1857.n) was first described by Pasteur in 1857.)
Bustamante 2008 Neurochem Res + (Age related changes in brain cortex NO met … Age related changes in brain cortex NO metabolism were investigated in mitochondria and cytosolic extracts from youth to adulthood. Decreases of 19%, 40% and 71% in NO production were observed in mitochondrial fractions from 3, 7, and 14 months old rats, respectively, as compared with 1-month-old rats. Decreased nNOS protein expression in 14 months old rats was also observed in mitochondria as compared with the nNOS protein expression in 1-month-old rats. Low levels of eNOS protein expression close to the detection limits and no iNOS protein expression were significantly detected in mitochondrial fraction for both groups of age. NO production in the cytosolic extracts also showed a marked decreasing tendency, showing higher levels than those observed in mitochondrial fractions for all groups of age. In the cytosolic extracts, however, the levels were stabilized in adult animals from 7 to 14 months. nNOS protein expression showed a similar age-pattern in cytosolic extracts for both groups of age, while the protein expression pattern for eNOS was higher expressed in adult rats (14 months) than in young animals. As well as in mitochondrial extracts iNOS protein expression was not significantly detected in cytosolic extracts at any age. RT-PCR assays indicated increased levels of nNOS mRNA in 1-month-old rats as compared with 14 months old rats, showing a similar pattern to that one observed for protein nNOS expression. A different aged pattern was observed for eNOS mRNA expression, being lower in 1-month-old rats as compared with 14 months old animals. iNOS mRNA was very low expressed in both groups of age, showing a residual iNOS mRNA that was not significantly detected. State 3 respiration rates were 78% and 85% higher when succinate and malate-glutamate were used as substrates, respectively, in 14 months rats as compared with 1-month-old rats. No changes were observed in state 4 respiration rates. These results could indicate 1 that nNOS and eNOS mRNA and protein expression can be age-dependent, and confirmed the nNOS origin for the mitochondrial NOS. During rat growth, the respiratory function seems to be modulated by NO produced by the different NOS enzymes: nNOS, eNOS and mtNOS present in the cytosol and in the mitochondria.nt in the cytosol and in the mitochondria.)
Santanasto 2016 Exp Gerontol + (Age related declines in walking performanc … Age related declines in walking performance may be partly attributable to skeletal muscle mitochondrial dysfunction as mitochondria produce over 90% of ATP needed for movement and the capacity for oxidative phosphorylation decreases with age.Participants were from two studies: an ancillary to the Lifestyle Interventions and Independence for Elders (LIFE) Study (n=33), which recruited lower functioning participants (Short Physical Performance Battery [SPPB], 7.8±1.2), and the Study of Energy and Aging-Pilot (SEA, n=29), which enrolled higher functioning (SPPB, 10.8±1.4). Physical activity was measured objectively using the Actigraph accelerometer (LIFE) and SenseWear Pro armband (SEA). Phosphocreatine recovery following muscle contraction of the quadriceps was measured using (31)P magnetic resonance spectroscopy and ATPmax (mM ATP/s) was calculated. Walking performance was defined as time (s) to walk 400m at a usual-pace. The cross-sectional association between mitochondrial function and walking performance was assessed using multivariable linear regression.Participants were 77.6±5.3years, 64.2% female and 67.2% white. ATPmax was similar in LIFE vs. SEA (0.52±0.14 vs. 0.55±0.14, p=0.31), despite different function and activity levels (1.6±2.2 vs.77.4±73.3min of moderate activity/day, p<0.01). Higher ATPmax was related to faster walk-time in SEA (r(2)=0.19, p=0.02,); but not the LIFE (r(2)<0.01, p=0.74) cohort.Mitochondrial function was associated with walking performance in higher functioning, active older adults, but not lower functioning, sedentary older adults.t not lower functioning, sedentary older adults.)
Spendiff 2014 Abstract MiP2014 + (Age related loss of independence and mobil … Age related loss of independence and mobility and an ill health are largely associated with sarcopenia, for which a prominent explanation is mitochondrial damage. Increases in mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction have been reported in aging skeletal muscle [1,2]. Master athletes (MAs) continue training and competing well into old age and represent an prominent model of healthy muscle aging [3]. The cellular mechanisms facilitating this achievement are currently unknown. Given their remarkable aging trajectory, it is reasonable to hypothesize that MAs have superior mitochondrial function and indices of mtDNA integrity. 15 world class elite MAs and 14 age-sex matched none-athlete controls (NAC), all over the age of 75, underwent muscle MRI scans to assess muscle mass and a biopsy of the vastus lateralis. mtDNA integrity was assessed using the duel cytochrome ''c'' oxidase/succinate dehydrogenase stain to ascertain the number of fibres with a respiratory system defect (RSD) and QPCR to provide an indication of mtDNA deletions and copy number. Three aspects of mitochondrial function were assessed in permeabilized myofibres: ROS production, respiration and calcium retention capacity. MAs had significantly more muscle mass than their sedentary counterparts, fewer myofibres with a RSD and an increased mtDNA copy number. However, there were very few differences in any of the three aspects of mitochondrial function examined. Therefore, while MAs have less RSD than NACs at the individual fibre level, this is not sufficient to result in an improvement in mitochondrial function, when studied at the whole muscle level. Thus a superior mitochondrial profile probably does not explain MAs’ remarkable muscle aging trajectory. However, in the presence of age related comorbidities the increased RSD may result in an exacerbation of these conditions in NACs. This data raises questions regarding the impact of age related mitochondrial changes on the muscle, as MAs, with the same level of mitochondrial function as controls, still displayed remarkable strength.rols, still displayed remarkable strength.)
Hashizume 2015 Sci Rep + (Age-associated accumulation of somatic mut … Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. We carried out reprogramming of human fibroblast lines derived from elderly subjects by generating their induced pluripotent stem cells (iPSCs), and examined another possibility, namely that these aging phenotypes are controlled not by mutations but by epigenetic regulation. Here, we show that reprogramming of elderly fibroblasts restores age-associated mitochondrial respiration defects, indicating that these aging phenotypes are reversible and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either the nuclear or the mitochondrial genome. Microarray screening revealed that epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in glycine production in mitochondria, is partly responsible for these aging phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented the expression of these aging phenotypes. the expression of these aging phenotypes.)
Bhaskaran 2020 Aging Cell + (Age-associated loss of muscle mass and fun … Age-associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice (Sod1-/- mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2- to 4-month-old) Sod1flox/SlickHCre mice with tamoxifen to generate i-mn-Sod1KO mice. CuZnSOD protein was 40-50% lower in neuronal tissue in i-mn-Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18- to 22-month-old i-mn-Sod1KO mice. By 24 months, 22% of NMJs in i-mn-Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal-specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.tional fibers past the maximum size of the motor unit.)
Bose 2020 Aging Cell + (Age-associated mitochondrial dysfunction a … Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group. In the old mice, SFN restored Nrf2 activity, mitochondrial function, cardiac function, exercise capacity, glucose tolerance, and activation/differentiation of skeletal muscle satellite cells. Our results suggest that the age-associated decline in Nrf2 signaling activity and the associated mitochondrial dysfunction might be implicated in the development of age-related disease processes. Therefore, the restoration of Nrf2 activity and endogenous cytoprotective mechanisms by SFN may be a safe and effective strategy to protect against muscle and heart dysfunction due to aging.muscle and heart dysfunction due to aging.)
Dias 2016 Neurobiol Aging + (Age-dependent changes in nitric oxide ((•) … Age-dependent changes in nitric oxide ((•)NO) concentration dynamics may play a significant role in both decaying synaptic and metabolic functions in Alzheimer's disease (AD). This neuromodulator acts presynaptically to increase vesicle release and glutamatergic transmission and also regulates mitochondrial function. Under conditions of altered intracellular redox environment, (•)NO may react and produce reactive species such as peroxynitrite. Using the triple transgenic mouse model of AD (3xTgAD), we investigated age-dependent changes in the glutamate-(•)NO axis in the hippocampus. Direct measurement of (•)NO concentration dynamics revealed a significant increase in N-methyl-D-aspartate type receptor-evoked peak (•)NO in the 3xTgAD model at an early age. Aging produced a decrease in peak (•)NO accompanied by significant decrease in production and decay rates in the transgenic model. Evaluation of energy metabolism revealed age-dependent decrease in basal oxygen consumption rate, a general decrease in mitochondrial oxidative phosphorylation parameters, and loss in mitochondrial sparing capacity in both genotypes. Finally, we observed age-dependent increase in 3-nitrotyrosine residues in the hippocampus, consistent with a putative shift in (•)NO bioactivity toward oxidative chemistry associated with neurotoxicity.Copyright © 2016 Elsevier Inc. All rights reserved. © 2016 Elsevier Inc. All rights reserved.)
Gioscia-Ryan 2015 Abstract MiPschool Greenville 2015 + (Age-related arterial endothelial dysfuncti … Age-related arterial endothelial dysfunction, characterized by a decline in endothelium-dependent dilation (EDD), is mediated largely by oxidative stress. Excessive levels of mitochondria-derived reactive oxygen species (mtROS), a hallmark of mitochondrial dysfunction, are an important contributor to tonic arterial oxidative stress-mediated suppression of EDD with aging [1]. In addition to baseline deficits in arterial function, aging may also be accompanied by reduced arterial resilience, i.e., the ability to withstand stress. Aging exacerbates the effects of common stressors such as a “Western”-style (high fat/high sugar) diet, hyperglycemia, and elevated low-density lipoprotein (LDL) cholesterol, such that the age- and stressor-associated impairments in arterial function are compounded [2]. However, whether declines in arterial mitochondrial health contribute to decreased resilience with aging is unknown. Aerobic exercise is a powerful intervention that restores baseline endothelial function with aging and improves mitochondrial health in many non-vascular tissues but the effects of exercise on arterial resilience and mitochondrial health with primary aging are unexplored. We tested the hypothesis that aging would be associated with reduced arterial mitochondrial health and impaired arterial resilience to acute stress, and that voluntary aerobic exercise initiated in late life would improve arterial mitochondrial health and increase resilience of aging arteries. Young (5 mo) and old (25 mo) male C57BL/6 mice were randomly assigned to either a sedentary cage control group (young and old control [YC, n=11 and OC, n=12]) or a voluntary aerobic exercise group (young and old voluntary wheel running [YVR, n=10 and OVR, n=11] for 10 weeks. After 10 weeks, endothelial function was assessed in isolated carotid arteries as EDD in response to increasing doses of acetylcholine (ACh). Arterial resilience was determined as the change in EDD response with ACh alone versus following acute application of a mitochondrial stressor (rotenone 0.5 µM, 40 min [1]) or a simulated “Western Diet (WD)” stressor (8 mM glucose + 160 µM palmitate; 40 min intraluminal infusion). The contribution of mtROS to the “WD” stress was determined by assessing EDD with “WD” in the presence of the mitochondria-specific antioxidant MitoQ (1 µM) [3]. Arterial mtROS production was assessed in aortic segments via electron paramagnetic resonance with the mitochondrial superoxide-specific spin probe mitoTEMPO-H. Arterial protein markers of mitochondrial health (PGC-1α, SIRT-3, Fis-1 [TTC11]) were assessed by Western blotting (normalized to GAPDH).by Western blotting (normalized to GAPDH).)

(Age-related arterial endothelial dysfunction, characterized by a decline)

Pharaoh 2019 Mol Neurobiol + (Age-related decline in circulating levels … Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.gies potentially by decreasing mitochondrial function.)
Egerman 2015 Cell Metab + (Age-related frailty may be due to decrease … Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-β molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia. blockade to treat age-related sarcopenia.)
Andersson 2011 Cell Metab + (Age-related loss of muscle mass and force … Age-related loss of muscle mass and force (sarcopenia) contributes to disability and increased mortality. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium release channel required for muscle contraction. RyR1 from aged (24 months) rodents was oxidized, cysteine-nitrosylated, and depleted of the channel-stabilizing subunit calstabin1, compared to RyR1 from younger (3-6 months) adults. This RyR1 channel complex remodeling resulted in "leaky" channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice. Treating aged mice with S107 stabilized binding of calstabin1 to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species (ROS), and enhanced tetanic Ca(2+) release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.es to age-related loss of muscle function.)
Joseph 2012 Aging Cell + (Age-related loss of muscle mass and streng … Age-related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high- and low-functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low-functioning elderly (LFE) participants when compared to young and high-functioning elderly (HFE) participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in COX activity. Levels of key metabolic regulators, SIRT3 and [[PGC-1α]] were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects, however no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery (PIM) components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways, and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.rmance observed in the elderly population.)
Ahn 2018 Redox Biol + (Age-related loss of skeletal muscle mass and contractile dysfunction, or sarcopenia, reduces independence and quality of life in the elderly and leads to increased risk of comorbidities...)
Ahn 2022 Aging Cell + (Age-related muscle atrophy and weakness, o … Age-related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle-specific overexpression of the mitochondrial H2O2 scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2O2 can prevent or delay the redox-dependent sarcopenia. Basal rates of H2O2 generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross-sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild-type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle-specific PRDX3 overexpression reduces mitochondrial H2O2 generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox-dependent sarcopenia.ion, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox-dependent sarcopenia.)
Paeaesuke 2015 Oxid Med Cell Longev + (Ageing is associated with suppressed regen … Ageing is associated with suppressed regenerative potential of muscle precursor cells due to decrease of satellite cells and suppressive intramuscular milieu on their activation, associated with ageing-related low-grade inflammation. The aim of the study was to characterize the function of oxidative phosphorylation (OXPHOS), glycolysis, adenylate kinase (AK), and creatine kinase (CK)-mediated systems in young and older individuals.Myoblasts were cultivated from biopsies taken by transcutaneous conchotomy from ''vastus lateralis'' muscle in young (20-29 yrs, n=7) and older (70-79 yrs, n=7) subjects. Energy metabolism was assessed in passages 2 to 6 by oxygraphy and enzyme analysis.In myoblasts of young and older subjects the rate of OXPHOS decreased during proliferation from passage 2 to 6. The total activities of CK and AK decreased. Myoblasts of passage 2 cultivated from young muscle showed higher rate of OXPHOS and activities of CK and AK compared to myoblasts from older subjects while hexokinase and pyruvate kinase were not affected by ageing.Proliferation of myoblasts ''in vitro'' is associated with down-regulation of OXPHOS and energy storage and transfer systems. Ageing ''in vivo'' exerts an impact on satellite cells which results in altered metabolic profile in favour of the prevalence of glycolytic pathways over mitochondrial OXPHOS of myoblasts.ys over mitochondrial OXPHOS of myoblasts.)
Paju 2014 Abstract MiP2014 + (Ageing is frequently associated with sarco … Ageing is frequently associated with sarcopenia, which has been attributed to low grade inflammation, suppressed regenerative potential of muscle precursor cells and homeostatic changes in the niches of satellite cells of old persons [1,2]. The aim of this study was to investigate mitochondrial function in primary cell cultures, derived from biopsies taken from young and old individuals.Primary muscle cell culture myoblasts, obtained from biopsies of vastus lateralis in young (19-29 y) and old (70-80 y) subjects, were purified with CD56 antibody microbeads on MACS and cultured in the presence of HGF. The cultures were stimulated with differentiation media supplement, insulin-transferrin-sodium selenite (ITS), for 6 days with one of cytokines IL1, IL6 or TNF-α. The function of respiratory complexes (OXPHOS) was assessed by high-resolution respirometry.The myoblasts cultivated from old individuals differentiated into myotubes markedly slower than myoblasts from young individuals in ITS medium (''P''<0.0001). The effect of IL-6 depended on donor age, as its effect on myoblast differentiation decreased with age. Treatment of human myoblasts with TNF-α and IL-1β increased the proliferation and blocked differentiation in the presence of ITS. The inhibitory effect of TNF-α and IL-1β on myotubes formation was mediated by down-regulation of mRNA levels of myogenin and muscle-specific isoforms of CK (CKM and CKMT2). The data on mitochondrial respiration revealed that IL-1β caused a significant decrease in mitochondrial Complex I- and II-linked respiration, normalized on cell protein content both in the myotubes of old and young individuals. This action of IL1-β was not seen when the respiratory results were normalized on citrate synthase activity, revealing the role of a decrease in mitochondrial content in these cells. TNF-α, on the contrary, caused a significant increase in mitochondrial Complex I- and II-linked respiration, normalized on protein in myotubes of old and young subjects. This action of TNF-α remained significant when respiration was normalized on citrate synthase activity. The mode of action of these pro-inflammatory cytokines on OXPHOS of muscle cell cultures was the same in both groups, young and old persons.Our data suggest that the myoblasts cultivated from biopsies of old individuals differentiate into myotubes slower than those from young individuals. The actions of pro-inflammatory cytokines on OXPHOS level of these cell cultures are different: IL-1β decreased, TNF-α stimulated but IL-6 exerted no alteration on OXPHOS activity, both in old or young individuals. The OXPHOS capacity in myogenic cell culture depends more on the mode of action of cytokine than the donor’s age.e of action of cytokine than the donor’s age.)
Gnaiger 2012 Abstract-FEPS-Santiago de Compostela + (Aging implicates a progressive decline in … Aging implicates a progressive decline in muscle mass and strength (sarcopenia) which is counteracted by strength training, and a decline of aerobic performance (muscle fatigability, reduced aerobic capacity and loss of mitochondrial power or OXPHOS capacity in muscle tissue). OXPHOS capacity is increased or maintained high by a life style involving endurance exercise and strength training [1]. Life style changes from the age of 20-30 years to the elderly, but is subject to change and intervention. Depending on group selection in cross-sectional studies, OXPHOS capacity declines from the age of 20-30 years [2,3], or is independent of age up to 80 years [4,5]. Independent of age, there is a strong decline of OXPHOS capacity in human vastus lateralis from BMI of 20 to 30 [6]. The relationship between BMI, training and OXPHOS capacity is also observed in horse skeletal muscle [7]. At a BMI >30, a minimum OXPHOS capacity is reached in human v. lateralis that may be characteristic of a low-grade inflammatory state (‘mitochondrial fever’). Onset of degenerative diseases (diabetes 2, neuromuscular degeneration, various cancers) and mitochondrial dysfunction interact in an amplification loop progressing slowly with age, such that cause and effect of mitochondrial dysfunction cannot be distinguished. Diminished antioxidant capacity at low mitochondrial density is an important mechanistic candidate in the state of mitochondrial fever.Contribution to K-Regio ''[[MitoCom_O2k-Fluorometer|MitoCom Tyrol]]''. # [[Pesta_2011_Am J Physiol Regul Integr Comp Physiol|Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E (2011) Similar qualitative and quantitative changes of mitochondrial respiration following strength and endurance training in normoxia and hypoxia in sedentary humans. Am J Physiol Regul Integr Comp Physiol 301:R1078–87.]]# Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS (2005) Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102:5618-23.# [[Joseph 2012 Aging Cell|Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, Aranda JM, Sandesara BD, Pahor M, Manini TM, Marzetti E, Leeuwenburgh C (2012) The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell 11:801-9.]]# Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, McConnell JP, Nair KS (2008) Endurance exercise as a countermeasure for aging. Diabetes 57:2933-42.# [[Larsen 2012 Acta Physiol (Oxf)|Larsen S, Hey-Mogensen M, Rabol R, Stride N, Helge JW, Dela F (2012) The influence of age and aerobic fitness: Effects on mitochondrial respiration in skeletal muscle. Acta Physiol (Oxf) 205:423-32.]]# [[Gnaiger 2009 Int J Biochem Cell Biol|Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837–45.]]# [[Votion_2012_PLoS One|Votion DM, Gnaiger E, Lemieux H, Mouithys-Mickalad A, Serteyn D (2012) Physical fitness and mitochondrial respiratory capacity in horse skeletal muscle. PLoS One 7:e34890.]]_2012_PLoS One|Votion DM, Gnaiger E, Lemieux H, Mouithys-Mickalad A, Serteyn D (2012) Physical fitness and mitochondrial respiratory capacity in horse skeletal muscle. PLoS One 7:e34890.]])
Reis 2016 Aging (Albany NY) + (Aging increases the risk of type 2 diabete … Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance.rolling metabolism and insulin resistance.)
Gregg 2016 Diabetes + (Aging is accompanied by impaired glucose h … Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure of insulin secretion from pancreatic β cells. To investigate the effects of age on β cell metabolism, we established a novel assay to directly image islet metabolism using NAD(P)H fluorescence lifetime imaging (FLIM). We determined that impaired mitochondrial activity underlies an age-dependent loss of insulin secretion in human islets. NAD(P)H FLIM revealed a comparable decline in mitochondrial function in the pancreatic islets of aged mice (≥ 24 months), resulting from 52% and 57% defects in flux through complex I and II of the electron transport chain. However, insulin secretion and glucose tolerance are preserved in aged mouse islets by the heightened metabolic sensitivity of the β cell triggering pathway, an adaptation clearly encoded in the metabolic and Ca2+ oscillations that trigger insulin release (Ca2+ plateau fraction: young, 0.211 ± 0.006; aged, 0.380 ± 0.007, P < 0.0001). This enhanced sensitivity is driven by a reduction in KATP channel conductance (diazoxide: young, 5.1 ± 0.2 nS; aged, 3.5 ± 0.5 nS, P < 0.01), resulting in a ∼2.8 mM left shift in the β cell glucose threshold. Our results demonstrate how mice, but not humans, are able to successfully compensate for age-associated metabolic dysfunction by adjusting their β cell glucose sensitivity, and highlight an essential mechanism for ensuring the maintenance of insulin secretion.© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.perly cited, the use is educational and not for profit, and the work is not altered.)
Goetzman 2023 Antioxidants (Basel) + (Aging is associated with a decline in mito … Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate and plays an essential role in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). The dysfunction of Complex II not only limits mitochondrial energy production; it may also promote oxidative stress, contributing, over time, to cellular damage, aging, and disease. Intriguingly, succinate, the substrate for Complex II which accumulates during mitochondrial dysfunction, has been shown to have widespread effects as a signaling molecule. Here, we review recent advances related to understanding the function of Complex II, succinate signaling, and their combined roles in aging and aging-related diseases.roles in aging and aging-related diseases.)
Eisenberg 2016 Nat Med + (Aging is associated with an increased risk … Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes ''in vivo'', coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.protection against cardiovascular disease.)
Boushel 2014 Pro Can Soc Exercise Physiol + (Aging is associated with diminished cardio … Aging is associated with diminished cardiovascular function and sarcopenia, and loss of muscle oxidative capacity is considered a salient feature of aging. While moderate-to-high intensity training evokes mitochondrial biogenesis in skeletal muscle, it remains unclear to what extent aging in itself or rather a lower training stimulus that accompanies aging contributes to loss of skeletal muscle mitochondrial function. To address this question leg muscle mitochondrial respiratory capacity in 8 older men (65±2 yrs) who had maintained road cycling training 200 km/week for 50 years was compared to that of 8 age-matched sedentary (UT) controls (67±1 yrs).V˙ O2 max was measured on a bicycle ergometer and a biopsy obtained from vastus lateralis muscle was permeabilized and prepared for high resolution respirometry (Oxygraph, Oroboros, AT). V˙ O2 max was substantially higher (p<0.05) in lifelong trained (45±2 ml/kg/min) compared to UT (27±2 ml/kg/min). Mitochondrial LEAK respiration was higher in ET, and Vmax of mitochondrial respiration (OXPHOS) with mixed substrates was 2-fold higher in the ET (132±6 pmol/sec/mg) compared to UT (72±4 pmol/sec/mg, p<0.01). Higher fatty acid oxidation and substrate control ratios in ET indicate regulatory changes in mitochondria in addition to a larger mitochondrial volume. The findings indicate that skeletal muscle mitochondrial respiratory capacity of ‘lifelong trained’ older males is retained at a level comparable to young athletic individuals, and suggest that decrements in aerobic performance with age are primarily attributed to diminished cardiovascular function.ttributed to diminished cardiovascular function.)
Rufini 2012 Genes Dev + (Aging is associated with impaired scavengi … Aging is associated with impaired scavenging of reactive oxygen species (ROS). Here, we show that TAp73, a p53 family member, protects against aging by regulating mitochondrial activity and preventing ROS accumulation. TAp73-null mice show more pronounced aging with increased oxidative damage and senescence. TAp73 deletion reduces cellular ATP levels, oxygen consumption, and mitochondrial complex IV activity, with increased ROS production and oxidative stress sensitivity. We show that the mitochondrial complex IV subunit cytochrome C oxidase subunit 4 (Cox4i1) is a direct TAp73 target and that Cox4i1 knockdown phenocopies the cellular senescence of TAp73-null cells. Results indicate that TAp73 affects mitochondrial respiration and ROS homeostasis, thus regulating aging.nd ROS homeostasis, thus regulating aging.)
No 2020 Pflugers Arch + (Aging is associated with vulnerability to … Aging is associated with vulnerability to cardiovascular diseases, and mitochondrial dysfunction plays a critical role in cardiovascular disease pathogenesis. Exercise training is associated with benefits against chronic cardiac diseases. The purpose of this study was to determine the effects of aging and treadmill exercise training on mitochondrial function and apoptosis in the rat heart. Fischer 344 rats were divided into young sedentary (YS; ''N'' = 10, 4 months), young exercise (YE; n''N''= 10, 4 months), old sedentary (OS; ''N'' = 10, 20 months), and old exercise (OE; ''N'' = 10, 20 months) groups. Exercise training groups ran on a treadmill at 15 m/min (young) or 10 m/min (old), 45 min/day, 5 days/week for 8 weeks. Morphological parameters, mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondria-mediated apoptosis were analyzed in cardiac muscle. Mitochondrial O2 respiratory capacity and Ca2+ retention capacity gradually decreased, and mitochondrial H2O2 emitting potential significantly increased with aging. Exercise training attenuated aging-induced mitochondrial H2O2 emitting potential and mitochondrial O2 respiratory capacity, while protecting Ca2+ retention in the old groups. Aging triggered imbalanced mitochondrial dynamics and excess mitophagy, while exercise training ameliorated the aging-induced imbalance in mitochondrial dynamics and excess mitophagy. Aging induced increase in Bax and cleaved caspase-3 protein levels, while decreasing Bcl-2 levels. Exercise training protected against the elevation of apoptotic signaling markers by decreasing Bax and cleaved caspase-3 and increasing Bcl-2 protein levels, while decreasing the Bax/Bcl-2 ratio and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive myonuclei. These data demonstrate that regular exercise training prevents aging-induced impairment of mitochondrial function and mitochondria-mediated apoptosis in cardiac muscles.ular exercise training prevents aging-induced impairment of mitochondrial function and mitochondria-mediated apoptosis in cardiac muscles.)
Daum 2013 Proc Natl Acad Sci U S A + (Aging is one of the most fundamental, yet … Aging is one of the most fundamental, yet least understood biological processes that affect all forms of eukaryotic life. Mitochondria are intimately involved in aging, but the underlying molecular mechanisms are largely unknown. Electron cryotomography of whole mitochondria from the aging model organism ''Podospora anserina'' revealed profound age-dependent changes in membrane architecture. With increasing age, the typical cristae disappear and the inner membrane vesiculates. The ATP synthase dimers that form rows at the cristae tips dissociate into monomers in inner-membrane vesicles, and the membrane curvature at the ATP synthase inverts. Dissociation of the ATP synthase dimer may involve the peptidyl prolyl isomerase cyclophilin D. Finally, the outer membrane ruptures near large contact-site complexes, releasing apoptogens into the cytoplasm. Inner-membrane vesiculation and dissociation of ATP synthase dimers would impair the ability of mitochondria to supply the cell with sufficient ATP to maintain essential cellular functions. to maintain essential cellular functions.)
Tyrrell 2019 Circ Res + (Aging is one of the strongest risk factors … Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. The objective was to determine if vascular aging prior to the induction of hyperlipidemia enhances atherogenesis. We analyzed the aortas of young and aged normolipidemic wild type (WT), disease free mice and found that aging led to elevated IL-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged WT mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis.Prior to hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.ia may reduce age-related atherosclerosis.)
Shields 2021 Front Cell Dev Biol + (Aging is the greatest risk factor for a mu … Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.ult to generalize across the tree of life.)
Dawson 2020 Exp Gerontol + (Aging is typically associated with a decli … Aging is typically associated with a decline in whole animal performance that ultimately contributes to death. It is suspected that a decline in ATP production leads to dysfunction in cellular processes, contributing to the decline in performance. Birds require large amounts of ATP to support physiological process, especially flight, which is one of the most energetically expensive forms of locomotion in the animal kingdom to sustain. Since the bulk of ATP production is coordinated through mitochondrial activity, we set out to explore mitochondrial function in young (~8 months) and old (~73 months) zebra finches (''Taeniopygia guttata''). We exploited the fact that avian red blood cells (RBCs) are nucleated and have functional mitochondria to explore the phenomenon of age-related decline in mitochondrial function without the need for terminal sampling. We found that RBCs from old zebra finches have lower flux control ratios (mitochondrial O2 consumption attributed to ATP production; 0.29-0.36-fold), exhibit higher respiration (1.4-fold), and significantly higher citrate synthase activity (1.4-fold) than young birds. Respiration rates normalized to citrate synthase activity suggest that mitochondrial quality is changing, as leak state is significantly lower (0.39-fold) in old zebra finches in comparison to young animals. Overall, our findings indicate a possible change in the function of mitochondria in older zebra finches, which may be associated with a corresponding increase in mitochondrial quantity, possibly to offset a decline in mitochondrial quality.Copyright © 2018. Published by Elsevier Inc.mall>Copyright © 2018. Published by Elsevier Inc.)
Pharaoh 2023 Geroscience + (Aging muscle experiences functional declin … Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, ''in vivo'' heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles.ves physiological function in old muscles.)
Bernhardt 2015 Sci Rep + (Aging of biological systems is accompanied … Aging of biological systems is accompanied by degeneration of mitochondrial functions. Different pathways are active to counteract the processes which lead to mitochondrial dysfunction. Mitochondrial dynamics, the fission and fusion of mitochondria, is one of these quality control pathways. Mitophagy, the controlled degradation of mitochondria, is another one. Here we show that these pathways are linked. A double deletion mutant of Saccharomyces cerevisiae in which two essential components of the fission and fusion machinery, Dnm1 and Mgm1, are simultaneously ablated, contain wild-type like filamentous mitochondria, but are characterized by impaired respiration, an increased sensitivity to different stressors, increased mitochondrial protein carbonylation, and a decrease in mitophagy and replicative lifespan. These data show that a balanced mitochondrial dynamics and not a filamentous mitochondrial morphotype per se is the key for a long lifespan and demonstrate a cross-talk between two different mitochondrial quality control pathways.nt mitochondrial quality control pathways.)
Hepple 2014 Abstract MiP2014 + (Aging of skeletal muscle is associated wit … Aging of skeletal muscle is associated with progressive atrophy, reaching clinically relevant thresholds in terms of weakness, mobility impairment and physical frailty in a significant fraction of individuals ≥80 y of age. Amongst the factors posited to be involved, mitochondrial alterations are implicated in the atrophy of aging muscle through recruitment of mitochondrial-mediated pathways of apoptosis and proteolysis. However, denervation is also known to recruit these same mitochondrial pathways. In view of the sporadic denervation that occurs in aging muscle, consideration of denervation’s role in recruitment of mitochondrial atrophy pathways is essential to identify relevant therapeutic targets. As such, this presentation will review our current evidence from human skeletal muscle biopsies across a range of ages and physical activity levels, examining the impact of aging on mitochondrial function and the role played by denervation across this continuum. As will be demonstrated, skeletal muscle mitochondrial alterations in septuagenarian subjects appears to be a primary event unrelated to denervation, where an increased susceptibility to mitochondrial permeability transition persists even in physically active subjects. In contrast, octogenarian subjects exhibit denervation-induced modulation of mitochondrial reactive oxygen species emission, suggesting failed reinnervation rather than mitochondrial dysfunction as a more appropriate therapeutic target when aging muscle atrophy becomes most clinically relevant. atrophy becomes most clinically relevant.)
Soares 2022 Geroscience + (Aging of the vasculature is characterized … Aging of the vasculature is characterized by endothelial dysfunction and arterial stiffening, two key events in the pathogenesis of cardiovascular disease (CVD). Treatment with sodium glucose transporter 2 (SGLT2) inhibitors is now known to decrease cardiovascular morbidity and mortality in type 2 diabetes. However, whether SGLT2 inhibition attenuates vascular aging is unknown. We first confirmed in a cohort of adult subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether SGLT2 inhibition with empagliflozin (Empa) ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. Specifically, we assessed mesenteric artery endothelial function and stiffness (via flow-mediated dilation and pressure myography mechanical responses, respectively) and aortic stiffness (''in vivo'' via pulse wave velocity and ''ex vivo'' via atomic force microscopy) in Empa-treated (14 mg/kg/day for 6 weeks) and control 80-week-old C57BL/6 J male mice. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Additionally, Empa-treated mice had greater vascular endothelial nitric oxide synthase activation, lower phosphorylated cofilin, and filamentous actin content, with downregulation of pathways involved in production of reactive oxygen species. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of CVD in older individuals.e progression of CVD in older individuals.)
Hagl 2016 Nutr Neurosci + (Aging represents a major risk factor for n … Aging represents a major risk factor for neurodegenerative diseases such as Alzheimer's disease. Mitochondria are significantly involved in both the aging process and neurodegeneration. One strategy to protect the brain and to prevent neurodegeneration is a healthy lifestyle including a diet rich in antioxidants and polyphenols. Rice bran extract (RBE) contains various antioxidants including natural vitamin E forms (tocopherols and tocotrienols) and gamma-oryzanol. In this work, we examined the effects of a stabilized RBE on mitochondrial function in 18-month-old Naval Medical Research Institute mice (340 mg/kg body weight/day), which received the extract for 3 weeks via oral gavage.Mitochondrial parameters were measured using high-resolution respirometry (Oroboros Oxygraph-2k), Western blot analysis, and photometric methods in dissociated brain cells, isolated mitochondria, and brain homogenate. Vitamin E concentrations in blood plasma and brain tissue were measured using HPLC with fluorescence detection. Aging leads to decreased mitochondrial function (decreased mitochondrial respiration and ATP production) and decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha). RBE administration increased alpha-tocopherol concentrations in the brain and compensated for age-related mitochondrial dysfunction by increasing mitochondrial respiration, membrane potential, PGC1alpha protein expression, and citrate synthase activity. Furthermore, resistance of brain cells to sodium nitroprusside-induced nitrosative stress was improved. According to these results, RBE is a promising candidate nutraceutical for the prevention of age-related neurodegenerative diseases.of age-related neurodegenerative diseases.)