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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).)
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.)

(Aging is associated with an increased risk of cardiovascular disease and)

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.)
Hagl 2016 Neuromolecular Med + (Aging represents a major risk factor for t … Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer's disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction ''in vitro'' and in short-term ''in vivo'' feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD.nd thereby delaying or even preventing AD.)
Reutzel 2018 Oxid Med Cell Longev + (Aging represents a major risk factor for d … Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer's disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.ergy metabolism in the brain of aged mice.)
Lee 2010 Cell Metab + (Aging-associated muscle insulin resistance … Aging-associated muscle insulin resistance has been hypothesized to be due to decreased mitochondrial function, secondary to cumulative free radical damage, leading to increased intramyocellular lipid content. To directly test this hypothesis, we examined both ''in vivo'' and ''in vitro'' mitochondrial function, intramyocellular lipid content, and insulin action in lean healthy mice with targeted overexpression of the human catalase gene to mitochondria (MCAT mice). Here, we show that MCAT mice are protected from age-induced decrease in muscle mitochondrial function (∼30%), energy metabolism (∼7%), and lipid-induced muscle insulin resistance. This protection from age-induced reduction in mitochondrial function was associated with reduced mitochondrial oxidative damage, preserved mitochondrial respiration and muscle ATP synthesis, and AMP-activated protein kinase-induced mitochondrial biogenesis. Taken together, these data suggest that the preserved mitochondrial function maintained by reducing mitochondrial oxidative damage may prevent age-associated whole-body energy imbalance and muscle insulin resistance.y imbalance and muscle insulin resistance.)
Cockova 2017 Thesis + (Aim of this thesis was to observe changes … Aim of this thesis was to observe changes in oxidative metabolism and expression of important neuroenergetic proteins in human neuroblastoma cell line SH-SY5Y due to inhibition of FTO. FTO is a RNA demethylase that uses N6-methyladenosine as substrate. Differences in enzyme expression are connected to a broad area of effects involving energy homeostasis.Mitochondria are the cellular powerhouses, a key elements in production of energy and metabolic substrates, yet a source of potentially dangerous reactive oxygen species (ROS) and analogous reactive molecules. In order to better understand FTO purpose in neuronal energetic metabolism, we examined mitochondrial respiratory chain. Using high-resolution respirometry we were capable of observing impairment in mitochondrial respiration after FTO inhibition. There was a considerable decline in endogenous respiration, maximal respiration rate and reserve capacity. In order to obtain a more detailed view into mitochondrial respiration, expression levels of electron-transport complexes were quantified by Western blot technique. A slight reduction was identified in subunits of complex I and IV. However, the most prominent alteration was seen in the complex II subunit. There were no differences in expression of complex III and ATP synthase subunits. Beside disrupted activity of electron-transport system, ROS production can reflect mitochondrial dysfunction. By using fluorescence probes, we managed to observe increased ROS production in cells treated with FTO inhibitor.Furthermore, we studied how FTO inhibition affects insulin signaling. Expression of selected proteins involved in insulin signaling was detected by Western blot. Increased levels of insulin receptor and insulin degrading enzyme accompanied FTO inhibition. Additionally, a decreased ratio of p-Akt/Akt and p-p38/p38 together with an elevated ratio of p-ERK/ERK was observed. A minimal difference was sighted in PI3K p110 expression or p-GSK3β/GSK3β ratio.Taken together, these results suggest a considerable link between FTO activity and neuronal signaling and metabolic actions. Further research could undoubtedly prove to be beneficial in gaining knowledge about bioenergetics processes in the nervous system.nergetics processes in the nervous system.)
Larsen 2009 Diabetologia + (Aim/hypothesis: The aim of the study was t … Aim/hypothesis: The aim of the study was to investigate mitochondrial function, fibre type distribution and substrate oxidation in arm and leg muscle during exercise in patients with type 2 diabetes and in obese and lean controls.Methods: Indirect calorimetry was used to calculate fat and carbohydrate oxidation during both progressive arm-cranking and leg-cycling exercises. Muscle biopsies from arm and leg were obtained. Fibre type, as well as O2 flux capacity of saponin-permeabilised muscle fibres were measured, the latter by high resolution respirometry, in patients with type 2 diabetes, age- and BMI-matched obese controls, and age-matched lean controls.Results: Fat oxidation was similar in the groups during either arm or leg exercise. During leg exercise at higher intensities, but not during arm exercise, carbohydrate oxidation was lower in patients with type 2 diabetes compared with the other groups. In patients with type 2 diabetes, ADP-stimulated state 3 respiration per mg muscle with parallel electron input from complex I+II was lower in ''m. vastus lateralis'' compared with obese and lean controls, whereas no differences between groups were present in ''m. deltoideus''. A higher percentage of type IIX fibres was seen in ''m. vastus lateralis'' in patients with type 2 diabetes compared with obese and lean controls, whereas no difference was found in the deltoid muscle.Conclusions/interpretation: This study demonstrates similar O2 flux capacity, fibre type distribution and carbohydrate oxidation in arm muscle in the groups despite the presence of attenuated values in leg muscle in patients with type 2 diabetes compared with obese and lean controls.tients with type 2 diabetes compared with obese and lean controls.)
Raboel 2009 J Clin Endocrinol Metabol + (Aim: Skeletal muscle mitochondrial content … Aim: Skeletal muscle mitochondrial content is reduced in type 2 diabetes mellitus (T2DM). Whether hyperglycemia inhibits mitochondrial biogenesis and/or function is unknown. This study examined the effect of different levels of glycemia on skeletal muscle mitochondrial function in patients with T2DM.Patients and Methods: Eleven patients with T2DM [9 males, 2 females; age, 52.8 ± 2.5 yr (mean ± SE); body mass index, 30.2 ± 1.1 kg/m2 ] in poor glycemic control were treated with insulin aspart and NPH insulin for a median period of 46 d (range, 31–59). Mitochondrial respiration and citrate synthase activity (a marker of mitochondrial content) were measured before and after treatment. Eleven healthy subjects (age, 53.3 ± 2.7 yr; body mass index, 30.6 ± 1.1 kg/m2) were included as controls.Results: Hemoglobin A1c (9.1 ± 0.5 to 7.5 ± 0.3%; P < 0.001) and fasting plasma glucose (12.7 ± 1.1 to 6.5 ± 0.3 mmol/liter; P < 0.001) were reduced after treatment. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls [substrates for complex I, 24% lower (P < 0.05); substrates for complex I+II, 17% lower (P < 0.05)]. Mitochondrial respiration and citrate synthase activity did not differ before and after improvements in glycemic control, but mitochondrial respiration correlated with fasting plasma glucose before (r2 = 0.53; P < 0.05) but not after treatment [r2 = 0.0024; not significant (NS)]. Mitochondrial respiration normalized to mitochondrial content did not differ between control subjects and patients with T2DM.Discussion: Mitochondrial respiration and content was not improved after significant improvements in glycemic control. However, severe hyperglycemia inhibited respiration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.ration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.)
Baron 2010 Thesis + (Aim: The aim of this thesis was the analys … Aim: The aim of this thesis was the analysis of copy number variations of themitochondrial DNA (mtDNA) in several tissues and cell types with regard to different mitochondrial associated disorders.Background: The mtDNA copy number can be reduced due to mutations in thenuclear encoded DNA polymerase g (POLG) or damages caused by deleteriousreactive oxygen species (ROS), which are created by the respiratory chain. Thisleads to the insufficient expression of mitochondrial encoded subunits of complexes of the oxidative phosphorylation system (OXPHOS). Consequently an impairment of the biochemical activity and integrity of the cells occurs.Methods: The quantification of the mtDNA was performed by quantitative PCR(qPCR). Biochemical activities were determined by enzymatic assays such as direct measurement of the citrate synthase (CS) activity or comprehensive measurement of the respiratory activity.Results: Mutations in the nuclear inherited gene POLG result in mtDNA depletion in mitochondrial disorders including a mild phenotype of progressive externalophthalmoplegia (PEO) with epilepsy/ataxia. A mtDNA depletion was detected indifferent tissues and cell types of Alpers-Huttenlocher patients with pathogenicnuclear mutations. The mtDNA copy number was reduced in specific hippocampalregions of temporal lobe epilepsy (TLE) patients with Ammons’ horn sclerosis (AHS)accompanied by a decreased CS activity. An ''in vitro'' reduction of the mtDNA in fibroblasts results in an impaired respiratory activity.Conclusions: The mtDNA content is proportional to the mitochondria content andthe energy demand of the respective tissue or cell type under normal conditions. A cell type- and tissue-specific depletion of the mtDNA can be present in several inherited and somatic mitochondrial disorders ''in vivo'' or can be generated by an ''in vitro'' system. The mtDNA depletion diminishes the biochemical activity and integrity of the cells and can contribute to the disease phenotype.d can contribute to the disease phenotype.)
Lai 2019 Acta Physiol (Oxf) + (Aim: The subsarcolemmal (SSM) and interfib … Aim: The subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in skeletal muscle appear to have distinct biochemical properties affecting metabolism in health and disease. The isolation of mitochondrial subpopulations has been a long-time challenge while the presence of a continuous mitochondrial reticulum challenges the view of distinctive SSM and IFM bioenergetics. Here, a comprehensive approach is developed to identify the best conditions to separate mitochondrial fractions.Methods: The main modifications to the protocol to isolate SSM and IFM from rat skeletal muscle were: (a) decreased dispase content and homogenization speed; (b) trypsin treatment of SSM fractions; (c) recentrifugation of mitochondrial fractions at low speed to remove subcellular components. To identify the conditions preserving mitochondrial function, integrity, and maximizing their recovery, microscopy (light and electron) were used to monitor effectiveness and efficiency in separating mitochondrial subpopulations while respiratory and enzyme activities were employed to evaluate function, recovery, and integrity.Results: With the modifications described, the total mitochondrial yield increased with a recovery of 80% of mitochondria contained in the original skeletal muscle sample. The difference between SSM and IFM oxidative capacity (10%) with complex-I substrate was significant only with a saturated ADP concentration. The inner and outer membrane damage for both subpopulations was <1% and 8%, respectively, while the respiratory control ratio was 16.Conclusion: Using a multidisciplinary approach, conditions were identified to maximize SSM and IFM recovery while preserving mitochondrial integrity, biochemistry, and morphology. High quality and recovery of mitochondrial subpopulations allow to study the relationship between these organelles and disease.ionship between these organelles and disease.)
Hedges IBEC2012 + (Aim: This study aimed to compare mitochond … Aim: This study aimed to compare mitochondrial oxygen consumption in C57BL/6J wild-type and myostatin-deficient mouse soleus and white gastrocnemius muscles.Methods: Muscles were obtained from 4 month-old male mice. Mass-specific oxygen consumption (pmol.O2/mg/sec) was measured in permeabilised muscle, using high-resolution respirometry (Oroboros Oxygraph-2k). Maximal activities of citrate synthase and lactate dehydrogenase were determined by spectrophotometry.Results: Myostatin-deficient soleus (n=6) consumed 20% more oxygen per mg than wild-type soleus (n=6) during oxidative phosphorylation. This was accompanied by greater citrate synthase and lactate dehydrogenase enzyme activity in myostatin-deficient soleus (29% and 80% respectively). Myostatin-deficient gastrocnemius (n=7) showed 26% lower oxygen consumption during uncoupled respiration, and 34% lower oxygen consumption when oxidising glycerol-3-phosphate compared to wild-type gastrocnemius (n=8). Citrate synthase activity was not significantly different and lactate dehydrogenase activity 26% greater in myostatin-deficient gastrocnemius compared to wild-type gastrocnemius.Conclusion: These data suggest that myostatin-deficiency exerts fiber-type specific effects on skeletal muscle mitochondrial function.on skeletal muscle mitochondrial function.)
Chu SRS 2011 + (Aim: To determine the impact of cold ischa … Aim: To determine the impact of cold ischaemia on hepatic mitochondrial function in University of Wisconsin (UW) solution in the setting of hepatic steatosis.Methods: Livers were harvested from 10-week old genetically obese (ob/ob, ''n'' = 9) or lean C57 control mice (''n'' = 9); and preserved in ice-cold UW solution. Mitochondrial function analysis was performed on permeabilised liver samples using a substrate and inhibitor titration protocol in conjunction with a high-resolution respirometer (OROBOROS® Oxygraph-2k) at multiple time-points over 24 h during cold ischemia (CI).Results: Ob/ob mice livers and control mice livers showed either severe (> 60%) or no macrovesicular steatosis respectively. Mitochondria from ob/ob mice livers demonstrated a faster and greater decrease in the percentage of respiration contributing to oxidative phosphorylation over 24 hours of cold storage compared to control mice. After 12 hours of CI, there was also an increased dependence on Complex II respiration relative to Complex I in ob/ob mice livers suggestive of Complex I damage and potential loss of key ATP synthesis efficiency.Conclusion: There was a time-dependant damage of hepatic mitochondrial function during CI. Steatotic livers demonstrated greater mitochondrial dysfunction during CI compared to lean livers.ysfunction during CI compared to lean livers.)
Bakkman 2007 ActaPhysiol + (Aim: To investigate if training during hyp … Aim: To investigate if training during hypoxia (H) improves the adaptation of muscle oxidative function compared with normoxic (N) training performed at the same relative intensity.Method: Eight untrained volunteers performed one-legged cycle training during 4 weeks in a low-pressure chamber. One leg was trained under N conditions and the other leg under hypobaric hypoxia (526 mmHg) at the same relative intensity as during N (65% of maximal power output, ''W''max). Muscle biopsies were taken from vastus lateralis before and after the training period. Muscle samples were analysed for the activities of oxidative enzymes [citrate synthase (CS) and cytochrome c oxidase (COX)] and mitochondrial respiratory function.Results: ''W''max increased with more than 30% over the training period during both N and H. CS activity increased significantly after training during N conditions (+20.8%, P < 0.05) but remained unchanged after H training (+4.5%, ns) with a significant difference between conditions (''P'' < 0.05 H vs. N). COX activity was not significantly changed by training and was not different between exercise conditions [+14.6 (N) vs. -2.3% (H), ns]. Maximal ADP stimulated respiration (state 3) expressed per weight of muscle tended to increase after N (+31.2%, ''P'' < 0.08) but not after H training (+3.2%, ns). No changes were found in state four respiration, respiratory control index, P/O ratio, mitochondrial Ca2+ resistance and apparent ''K''m for oxygen.Conclusion: The training-induced increase in muscle oxidative function observed during N was abolished during H. Altitude training may thus be disadvantageous for adaptation of muscle oxidative function.ng may thus be disadvantageous for adaptation of muscle oxidative function.)
Cour 2014 J Cardiovasc Pharmacol Ther + (Aim: To investigate whether slight variati … Aim: To investigate whether slight variations in core temperature prior to cardiac arrest (CA) influence short-term outcomes and mitochondrial functions.Three groups of New Zealand White rabbits (n = 12/group) were submitted to 15 minutes of CA at 38°C (T-38 group), 39°C (T-39), or 40°C (T 40) and 120 minutes of reperfusion. A Sham-operated group (n = 6) underwent only surgery. Restoration of spontaneous circulation (ROSC), survival, hemodynamics, and pupillary reactivity were recorded. Animals surviving to the end of the observation period were euthanized to assess fresh brain and heart mitochondrial functions (permeability transition and oxidative phosphorylation). Markers of brain and heart damages were also measured.The duration of asphyxia required to induce CA was significantly lower in the T-40 group when compared to the T-38 group (''p''<.05). The rate of ROSC was >80% in all groups (''p''=nonsignificant [ns]). Survival significantly differed among the T-38, T-39, and T-40 groups: 10 (83%) of 12, 7 (58%) of 12, and 4 (33%) of 12, respectively (log-rank test, ''p''=.027). At the end of the protocol, none of the animals in the T-40 group had pupillary reflexes compared to 8 (67%) of 12 in the T-38 group (''p''<.05). Troponin and protein S100B were significantly higher in the T-40 versus T-38 group (''p''<.05). Cardiac arrest significantly impaired both inner mitochondrial membrane integrity and oxidative phosphorylation in all groups. Brain mitochondria disorders were significantly more severe in the T-40 group compared to the T-38 group (''p''< .05).Small changes in body temperature prior to asphyxial CA significantly influence brain mitochondrial functions and short-term outcomes in rabbits.tochondrial functions and short-term outcomes in rabbits.)
Orynbayeva 2015 Nanomedicine (Lond) + (Aim: To successfully translate magneticall … Aim: To successfully translate magnetically mediated cell targeting from bench to bedside, there is a need to systematically assess the potential adverse effects of magnetic nanoparticles (MNPs) interacting with ‘therapeutic’ cells. Here, we examined in detail the effects of internalized polymeric MNPs on primary rat endothelial cells’ structural intactness, metabolic integrity and proliferation potential.Materials & methods: The intactness of cytoskeleton and organelles was studied by fluorescentconfocal microscopy, flow cytometry and high-resolution respirometry. Results: MNPloaded primary endothelial cells preserve intact cytoskeleton and organelles, maintain normal rate of proliferation, calcium signaling and mitochondria energy metabolism.Conclusion: This study provides supportive evidence that MNPs at doses necessaryfor targeting did not induce significant adverse effects on structural integrity and functionality of primary endothelial cells – potential cell therapy vectors.helial cells – potential cell therapy vectors.)