Exercise training improves vascular mitochondrial function

Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels of peroxisome proliferative activated receptor-γ coactivator-1α and the downstream targets cytochrome c oxidase subunit IV isoform 1, isocitrate dehydrogenase ( Idh) 2, and Idh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser1177), and suppressed reactive oxygen species generation (all P < 0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared with SED mice, and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function.

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Vascular mitochondrial respiratory function: the impact of advancing age

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00324.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. H1660-H1669 ◽

Cited By ~ 5

Author(s):

Soung Hun Park ◽

Oh Sung Kwon ◽

Song-Young Park ◽

Joshua C. Weavil ◽

Robert H. I. Andtbacka ◽

...

Keyword(s):

Oxidative Coupling ◽

Respiratory Function ◽

Complex I ◽

Coupling Efficiency ◽

Middle Aged ◽

Mitochondrial Content ◽

Respiratory Capacity ◽

Age Related ◽

The Impact ◽

Mitochondrial Respiratory

Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I + II (CI+II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s−1·mg−1 and CI+II: 12.4 ± 0.8 pmol·s−1·mg−1, P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s−1·mg−1 and CI+II: 8.3 ± 0.5 pmol·s−1·mg−1) and old (CI: 7.2 ± 0.4 pmol·s−1·mg−1 and CI+II: 7.6 ± 0.5 pmol·s−1·mg−1) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [ r = −0.56 (CI), r = −0.7 (CI+II), and r = 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = −0.71, P < 0.05). As CS activity was inversely correlated with age ( r = −0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s−1·mg−1·U CS−1, P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s−1·mg−1·U CS−1, respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.

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High aerobic exercise capacity predicts increased mitochondrial response to exercise training

European Heart Journal ◽

10.1093/ehjci/ehaa946.3607 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Schwarzer ◽

S Zeeb ◽

E Heyne ◽

L.G Koch ◽

S.L Britton ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Exercise Training ◽

Aerobic Exercise ◽

Exercise Capacity ◽

Mitochondrial Function ◽

Citrate Synthase ◽

Respiratory Capacity ◽

The Impact ◽

Mitochondrial Respiratory

Abstract Low exercise capacity is a strong predictor of all-cause cardiovascular mortality and morbidity. In contrast, high exercise capacity is protective and “physical fitness” is considered beneficial. These effects seem to be mediated through mitochondrial function. Importantly, exercise capacity consists of an intrinsic (genetic) and an extrinsic (exercise, environmental) part. In humans, these two parts cannot be truly separated. The rat model of high (HCR) and low (LCR) capacity runners allows to distinguish between the two parts. We assessed mitochondrial function in this model, specifically investigating the impact of exercise training on mitochondrial respiratory capacity. HCR and LCR were divided into control and exercised groups. Exercise capacity was determined individually using a ramped test. Animals were trained five times a week for four weeks on a treadmill. Mitochondria were isolated from heart, M. gastrocnemius and liver. Citrate synthase activity and protein content were determined photometrically and respiratory capacity was measured using a Clark-type electrode. At the same age and tibia length, LCR-C were heavier and had a lower heart to body weight ratio than HCR-C. Citrate synthase activity was lower in skeletal muscle of LCR but cardiac citrate synthase was not different between sedentary HCR and LCR. Respiratory capacity in heart and liver was not different between sedentary HCR and LCR but was lower in skeletal muscle in LCR compared to HCR with all selected substrates (glutamate: 86,0±17,6 vs. 63,7±8,0; succinate: 203±19 vs. 136±17 nAO/min/mg Protein). Exercise training led to an increase in body weight in HCR but did not change body weight in LCR. Similarly, gastrocnemius and soleus weights only increased with exercise in HCR. Exercise led to an increase in citrate synthase activity in hearts of HCR (0,78±0,07 vs. 1,58±0,45 U/mg Protein) but not of LCR. Consistently, mitochondrial respiratory capacity was found increased in HCR with exercise in heart with all substrates (glutamate: 261±43 vs. 305±35; succinate 417±32 vs. 539±65 nAO/min/mg Protein). Liver was not affected by exercise. Conclusion Our data suggest that genetic predisposition for aerobic capacity additionally affects the response of mitochondria to exercise. Thus, it may be possible that the “born runner” benefits more from aerobic exercise training than the “less genetically equipped counterpart”. Funding Acknowledgement Type of funding source: None

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Sexual dimorphism in human skeletal muscle mitochondrial bioenergetics in response to type 1 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00411.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. E44-E51 ◽

Cited By ~ 1

Author(s):

Cynthia M. F. Monaco ◽

Catherine A. Bellissimo ◽

Meghan C. Hughes ◽

Sofhia V. Ramos ◽

Robert Laham ◽

...

Keyword(s):

Skeletal Muscle ◽

Type 1 Diabetes ◽

Sexual Dimorphism ◽

Respiratory Function ◽

Complex I ◽

Mitochondrial Protein ◽

Mitochondrial Bioenergetics ◽

The Impact ◽

Mitochondrial Respiratory

Sexual dimorphism in mitochondrial respiratory function has been reported in young women and men without diabetes, which may have important implications for exercise. The purpose of this study was to determine if sexual dimorphism exists in skeletal muscle mitochondrial bioenergetics in people with type 1 diabetes (T1D). A resting muscle microbiopsy was obtained from women and men with T1D ( n = 10/8, respectively) and without T1D (control; n = 8/7, respectively). High-resolution respirometry and spectrofluorometry were used to measure mitochondrial respiratory function, hydrogen peroxide (mH2O2) emission and calcium retention capacity (mCRC) in permeabilized myofiber bundles. The impact of T1D on mitochondrial bioenergetics between sexes was interrogated by comparing the change between women and men with T1D relative to the average values of their respective sex-matched controls (i.e., delta). These aforementioned analyses revealed that men with T1D have increased skeletal muscle mitochondrial complex I sensitivity but reduced complex II sensitivity and capacity in comparison to women with T1D. mH2O2 emission was lower in women compared with men with T1D at the level of complex I (succinate driven), whereas mCRC and mitochondrial protein content remained similar between sexes. In conclusion, women and men with T1D exhibit differential responses in skeletal muscle mitochondrial bioenergetics. Although larger cohort studies are certainly required, these early findings nonetheless highlight the importance of considering sex as a variable in the care and treatment of people with T1D (e.g., benefits of different exercise prescriptions).

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Exercise does not improve insulin resistance and mitochondrial characteristics together

Journal of Endocrinology ◽

10.1530/joe-21-0242 ◽

2021 ◽

Author(s):

Amanda J Genders ◽

Jujiao Kuang ◽

Evelyn C Marin ◽

Nicholas J Saner ◽

Javier Botella ◽

...

Keyword(s):

Insulin Resistance ◽

Exercise Training ◽

Protein Expression ◽

Respiratory Function ◽

Citrate Synthase ◽

Whole Body ◽

Chow Diet ◽

Mitochondrial Content ◽

Insulin Tolerance ◽

Mitochondrial Respiratory

The aim of this study was to investigate the relationship between mitochondrial content and respiratory function and whole-body insulin resistance in high fat diet (HFD) fed rats. Male Wistar rats were given either a chow diet or a HFD for 12 weeks. After four weeks of the dietary intervention, half of the rats in each group began eight weeks of interval training. In vivo glucose and insulin tolerance were assessed. Mitochondrial respiratory function was assessed in permeabilised soleus and white gastrocnemius (WG) muscles. Mitochondrial content was determined by measurement of citrate synthase (CS) activity and protein expression of components of the electron transport system (ETS). We found HFD rats had impaired glucose and insulin tolerance but increased mitochondrial respiratory function and increased protein expression of components of the ETS. This was accompanied by an increase in CS activity in WG. Exercise training improved glucose and insulin tolerance in the HFD rats. Mitochondrial respiratory function was increased with exercise training in the chow fed animals in soleus muscle. This exercise effect was absent in the HFD animals. In conclusion, exercise training improved insulin resistance in HFD rats, but without changes in mitochondrial respiratory function and content. The lack of an association between mitochondrial characteristics and whole-body insulin resistance was reinforced by the absence of strong correlations between these measures. Our results suggest that improvements in mitochondrial respiratory function and content are not responsible for improvements of whole-body insulin resistance in HFD rats.

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Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00158.2021 ◽

2021 ◽

Vol 321 (5) ◽

pp. R687-R698

Author(s):

Matthew T. Lewis ◽

Gregory M. Blain ◽

Corey R. Hart ◽

Gwenael Layec ◽

Matthew J. Rossman ◽

...

Keyword(s):

Skeletal Muscle ◽

High Intensity ◽

Respiratory Function ◽

Complex I ◽

High Intensity Exercise ◽

Respiratory Capacity ◽

Metabolic Perturbation ◽

Exercise Induced ◽

Mitochondrial Respiratory

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: −67% vs. −82%, Pi: 353% vs. 534%, pH: −0.22 vs. −0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (−3% and −36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (−15% and −33%), complex II (−36% and −23%), complex I + II (−31% and −20%), and state 3CI+CII control ratio (−24% and −39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

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Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

Scientific Reports ◽

10.1038/s41598-021-81846-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Liselotte Bruun Christiansen ◽

Tine Lovsø Dohlmann ◽

Trine Pagh Ludvigsen ◽

Ewa Parfieniuk ◽

Michal Ciborowski ◽

...

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Function ◽

Citrate Synthase ◽

Obese Group ◽

Control Group ◽

Dependent Manner ◽

Respiratory Capacity ◽

Protein Carbonyl Content ◽

Functional Changes ◽

Mitochondrial Respiratory

AbstractStatins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

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Abstract 102: Time-of-intake Regulates Glucocorticoid Pharmacology Of Cardiac Bioenergetics

Circulation Research ◽

10.1161/res.129.suppl_1.102 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Mattia Quattrocelli ◽

Michelle Wintzinger ◽

Karen Miz

Keyword(s):

Ex Vivo ◽

Gene Knockout ◽

Heart Tissue ◽

Functional Coupling ◽

Specific Gene ◽

Heart Metabolism ◽

Respiratory Capacity ◽

Circadian Time ◽

The Impact ◽

Mitochondrial Respiratory

Glucocorticoid steroids are circadian regulators of energy balance. However, the specific direct effects of glucocorticoids on heart metabolism remain unresolved. Moreover, the impact of circadian time-of-intake on glucocorticoid pharmacology is still unknown. Here, we investigated whether circadian time of exposure gates the effects of synthetic glucocorticoids on heart bioenergetics. We compared the effects of diurnal versus nocturnal glucocorticoids in heart tissue and mitochondria from wildtype mice, controlling the subjective circadian time of drug injection. To avoid interferences from other tissues, we developed an ex vivo system to interrogate the mitochondrial respiratory capacity rate (state III/state IV) in isolated hearts. We found that diurnal but not nocturnal pulse of the glucocorticoid prednisone increased the mitochondrial respiratory capacity rate in heart. This correlated with circadian-restricted effects on mitochondrial abundance. This was remarkable as it contrasts the circadian fluctuations of endogenous glucocorticoids. Using transgenic mice with inducible cardiac-specific gene knockout, we found that the bioenergetic effects of diurnal-restricted prednisone were dependent on the glucocorticoid receptor and its co-factor Kruppel-like factor 15. Considering the bioenergetic decline that hallmarks the aging heart, we asked whether these circadian-gated effects were applicable to aged mice. We therefore treated 24 months-old mice for 12 weeks with a diurnal-restricted regimen of prednisone. Compared to vehicle, diurnal prednisone increased mitochondrial respiration along with NAD + and ATP content in aged hearts. Moreover, lipidomic profiling of myocardial tissue showed that the vast majority of lipids were downregulated after treatment, including triacylglycerols, suggesting a functional coupling between lipid utilization and mitochondrial oxidation in treated hearts. We also found that diurnal-restricted prednisone rescued bioenergetics and improved function in diabetic hearts from db/db mice. In summary, our data indicate that glucocorticoids regulate cardiac bioenergetics according to circadian-time of intake, supporting a role for chrono-pharmacology in aged and diabetic hearts.

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S4/4 Mammalian complex I: A regulable and vulnerable pacemaker in mitochondrial respiratory function

Biochimica et Biophysica Acta (BBA) - Bioenergetics ◽

10.1016/j.bbabio.2008.05.135 ◽

2008 ◽

Vol 1777 ◽

pp. S33

Author(s):

Sergio Papa ◽

Domenico De Rasmo ◽

Salvatore Scacco ◽

Anna Signorile ◽

Zuzana Technikova-Dobrova ◽

...

Keyword(s):

Respiratory Function ◽

Complex I ◽

Mitochondrial Respiratory

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An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

10.20944/preprints201909.0043.v3 ◽

2020 ◽

Author(s):

Daniel Missailidis ◽

Sarah Annesley ◽

Claire Allan ◽

Oana Sanislav ◽

Brett Lidbury ◽

...

Keyword(s):

Steady State ◽

Fatty Acid ◽

Mitochondrial Function ◽

Complex I ◽

Atp Synthesis ◽

Beta Oxidation ◽

Respiratory Capacity ◽

Respiratory Complexes ◽

Stress Sensing ◽

Mitochondrial Respiratory

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolising patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signalling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

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Age-related Attenuation of Isoflurane Preconditioning in Human Atrial Cardiomyocytes

Anesthesiology ◽

10.1097/aln.0b013e318167af2d ◽

2008 ◽

Vol 108 (4) ◽

pp. 612-620 ◽

Cited By ~ 47

Author(s):

Yasushi Mio ◽

Martin W. Bienengraeber ◽

Jasna Marinovic ◽

David D. Gutterman ◽

Mladen Rakic ◽

...

Keyword(s):

Cell Death ◽

Respiratory Function ◽

Right Atrial ◽

Channel Activity ◽

Age Related ◽

Isolated Myocardium ◽

The Impact ◽

Mitochondrial Respiratory

Background Clinical trials suggest that anesthetic-induced preconditioning (APC) produces cardioprotection in humans, but the mechanisms of APC and significance of aging for APC in humans are not well understood. Here, the impact of age on the role of two major effectors of APC, mitochondria and sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channels, in preconditioning of the human atrial myocardium were investigated. Methods Right atrial appendages were obtained from adult patients undergoing cardiac surgery and assigned to mid-aged (MA) and old-aged (OA) groups. APC was induced by isoflurane in isolated myocardium and isolated cardiomyocytes. Mitochondrial oxygen consumption measurements, myocyte survival testing, and patch clamp techniques were used to investigate mitochondrial respiratory function and sarcKATP channel activity. Results After in vitro APC with isoflurane, the respiratory function of isolated mitochondria was better preserved after hypoxia-reoxygenation stress in MA than in OA. In isolated intact myocytes, APC significantly decreased oxidative stress-induced cell death in MA but not in OA, and isoflurane protection from cell death was attenuated by the sarcKATP channel inhibitor HMR-1098. Further, the properties of single sarcKATP channels were similar in MA and OA, and isoflurane sensitivity of pinacidil-activated whole cell KATP current was no different between MA and OA myocytes. Conclusion Anesthetic-induced preconditioning with isoflurane decreases stress-induced cell death and preserves mitochondrial respiratory function to a greater degree in MA than in OA myocytes; however, sarcKATP channel activity is not differentially affected by isoflurane. Therefore, effectiveness of APC in humans may decrease with advancing age partly because of altered mitochondrial function of myocardial cells.

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