Mitochondrial Oxidative Capacity Research Articles

Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

ObjectiveObesity and insulin resistance greatly increase the risk of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). We have previously discovered that whole-body and adipocyte-specific Ip6k1deletion protects mice from high-fat-diet-induced obesity and insulin resistance due to improved adipocyte thermogenesis and insulin signaling. Here, we aimed to determine the impact of hepatocyte-specific and whole-body Ip6k1 deletion (HKO and Ip6k1-KO or KO) on liver metabolism and NAFLD/NASH. MethodsBody weight and composition; energy expenditure; glycemic profiles; and serum and liver metabolic, inflammatory, fibrotic and toxicity parameters were assessed in mice fed Western and high-fructose diet (HFrD) (WD: 40% kcal fat, 1.25% cholesterol, no added choline and HFrD: 60% kcal fructose). Mitochondrial oxidative capacity was evaluated in isolated hepatocytes. RNA-Seq was performed in liver samples. Livers from human NASH patients were analyzed by immunoblotting and mass spectrometry. ResultsHKO mice displayed increased hepatocyte mitochondrial oxidative capacity and improved insulin sensitivity but were not resistant to body weight gain. Improved hepatocyte metabolism partially protected HKO mice from NAFLD/NASH. In contrast, enhanced whole-body metabolism and reduced body fat accumulation significantly protected whole-body Ip6k1-KO mice from NAFLD/NASH. Mitochondrial oxidative pathways were upregulated, whereas gluconeogenic and fibrogenic pathways were downregulated in Ip6k1-KO livers. Furthermore, IP6K1 was upregulated in human NASH livers and interacted with the enzyme O-GlcNAcase that reduces protein O-GlcNAcylation. Protein O-GlcNAcylation was found to be reduced in Ip6k1-KO and HKO mouse livers. ConclusionPleiotropic actions of IP6K1 in the liver and other metabolic tissues mediate hepatic metabolic dysfunction and NAFLD/NASH, and thus IP6K1 deletion may be a potential treatment target for this disease.

Statin Intolerance and Noncompliance: An Empiric Approach

Statin Intolerance and Noncompliance: An Empiric Approach

Skeletal Muscle Adaptations to Exercise Training in Young and Aged Horses.

In aged humans, low-intensity exercise increases mitochondrial density, function and oxidative capacity, decreases the prevalence of hybrid fibers, and increases lean muscle mass, but these adaptations have not been studied in aged horses. Effects of age and exercise training on muscle fiber type and size, satellite cell abundance, and mitochondrial volume density (citrate synthase activity; CS), function (cytochrome c oxidase activity; CCO), and integrative (per mg tissue) and intrinsic (per unit CS) oxidative capacities were evaluated in skeletal muscle from aged (n = 9; 22 ± 5 yr) and yearling (n = 8; 9.7 ± 0.7 mo) horses. Muscle was collected from the gluteus medius (GM) and triceps brachii at wk 0, 8, and 12 of exercise training. Data were analyzed using linear models with age, training, muscle, and all interactions as fixed effects. At wk 0, aged horses exhibited a lower percentage of type IIx (p = 0.0006) and greater percentage of hybrid IIa/x fibers (p = 0.002) in the GM, less satellite cells per type II fiber (p = 0.03), lesser integrative and intrinsic (p 0.04) CCO activities, lesser integrative oxidative phosphorylation capacity with complex I (PCI; p = 0.02) and maximal electron transfer system capacity (ECI+II; p = 0.06), and greater intrinsic PCI, ECI+II, and electron transfer system capacity with complex II (ECII; p 0.05) than young horses. The percentage of type IIx fibers increased (p < 0.0001) and of type IIa/x fibers decreased (p = 0.001) in the GM, and the number of satellite cells per type II fiber increased (p = 0.0006) in aged horses following exercise training. Conversely, the percentage of type IIa/x fibers increased (p ≤ 0.01) and of type IIx fibers decreased (p ≤ 0.002) in young horses. Integrative maximal oxidative capacity (p ≤ 0.02), ECI+II (p ≤ 0.07), and ECII (p = 0.0003) increased for both age groups from wk 0 to 12. Following exercise training, aged horses had a greater percentage of IIx (p ≤ 0.002) and lesser percentage of IIa/x fibers (p ≤ 0.07), and more satellite cells per type II fiber (p = 0.08) than young horses, but sustained lesser integrative and intrinsic CCO activities (p 0.04) and greater intrinsic PCI, ECI+II, and ECII (p 0.05). Exercise improved mitochondrial measures in young and aged horses; however, aged horses showed impaired mitochondrial function and differences in adaptation to exercise training.

Time dependent deterioration of mitochondrial oxidative capacity in heart transplantat recipients with type 2 diabetes mellitus

Abstract Background Diabetic cardiomyopathy is defined as Heart failure in patients with Type 2 Diabetes (T2DM) in absence of traditional risk factors. Following HTX, a substantial number of recipients develop insulin resistance or T2DM, associated with cardiac allograft vasculopathy and with increased mortality. Recently we have shown that endomyocardial biopsies of heart transplant (HTX) recipients with T2DM express reduced mitochondrial respiration. Purpose The current study analyses time depended impact of T2DM on myocardial mitochondrial respiration of a priorly non-diabetic heart. We hypothesized that myocardial mitochondrial oxidative phosphorylation capacity declines in patients with T2DM compared to glucose tolerant heart transplant recipients and that reduced mitochondrial respiration leads to impairment of cardiac function. Methods We included 101 HTX recipients who underwent routine endomyocardial biopsy. Patients with T1DM or a Donor with DM were excluded. Patients were classified according to criteria of the American Diabetes Association as non-diabetic (n=23), prediabetic (n=38) or T2DM (n=40), by either Fasting Plasma Glucose, 2h Plasma Glucose, HbA1c or intake of antidiabetic medication. We performed ex vivo high resolution respirometry on permeabilized fibres to assess myocardial mitochondrial respiration. Left ventricular ejection fraction (LV-EF) was assessed by cardiac-MRI or Echocardiography. Results Groups were of comparable age (p=0.06), sex (p=0.25) and time since HTX (p=0.91). Mean time since HTX was 29 months. Current rejection episodes (p=0.37) or corticoid pulse therapy (p=0.46) did not significantly differ between groups. Linear regression in T2DM patients revealed an inverse relationship between time since HTX and mitochondrial respiration at state III conditions supported by the substrates octanoyl-carnitine and ADP (R2=0.16, F(1,38)=6.97, p=0.01). Regression analyses for non-DM group and Prediabetes group revealed no significant relationship between time since HTX and mitochondrial function (non-DM: R2=0.04, F(1,21)=0.9, p=0.35; Prediabetes: R2=0.01, F(1,36)=0.27, p=0.61). Exclusion of patients with cellular allograft rejection (ISHLT ≥1) or of patients with recent corticoid pulse therapy did not alter these results. Linear correlation revealed a significant relationship (r=0.33, p=0.04) between declining mitochondrial state III respiration and left ventricular ejection fraction (n=39), suggesting associated functional consequences. Conclusions Our results suggest a T2DM associated decline of mitochondrial oxidative capacity in HTX recipients. Reduced mitochondrial respiration is associated to lower LV-EF. Targeting mitochondrial respiration might be a promising novel therapeutic approach to address T2DM associated mortality. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Research Counsil

NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults

BackgroundBoosting NAD+ via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. ObjectivesWe investigated the efficacy of NAD+-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. MethodsA randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m2]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD+ concentrations, were analyzed accordingly. ResultsFollowing supplementation, skeletal muscle NAD+ concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD+-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD+ metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD+-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. ConclusionsOur findings are consistent with previous findings on NAD+ efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD+-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034.

Synthesis of Ziziphus spina-christi (Jujube) Root Methanol Extract Loaded Functionalized Silver Nanoparticle (ZS-Ag-NPs); Physiochemical Characterization and Effect of ZS-Ag-NPs on Adipocyte Maturation, Adipokine and Vascular Smooth Muscle Cell Interaction.

In this research, a simple, green approach was employed to synthesize silver nanoparticles with the aid of Ziziphus spina-christi (L.) methanol root extract, which can act as a reducing, capping agent to treat obesity and inflammation. Globally, Ziziphus spina-christi (Jujube) root is used in traditional therapy as a lipolysis promoter. GC-MS results confirmed the availability of kaempferol (flavonol), cannabinol and indole-3-carboxylic acid in Ziziphus spina-christi root methanol extract (ZSE). ZSE silver nanoparticles (ZS-Ag-NPs) were synthesized and their effect on mitochondrial fatty acid oxidation capacity and adipokine levels in maturing adipocytes were analyzed. Maturing adipocytes treated with 0.4 µg/dL of ZSE and ZS-Ag-NPs significantly reduced the lipid content in adipocytes by 64% and 82%, respectively. In addition, lipolysis-related genes such as LPL (1.9 fold), HSL (2.3 fold), PGC-1α (3 fold), UCP-1 (4.1 fold), PRDM16 (2 fold) and PPARα (2.7 fold) increased significantly in ZS-Ag-NPs treated maturing adipocytes. The ZS-Ag-NPs treatment significantly decreased insulin resistance and metabolic inflammation-related LTB4-R, TNF-α, IL-4 and STAT-6 mRNA levels. Mitochondrial thermogenesis stimulating capacity of ZS-Ag-NPs was further confirmed by the significantly enhanced CREB-1 and AMPK protein levels in adipocytes. Furthermore, ZS-Ag-NPs treated adipokines (condition media, CM) were treated with human umbilical vein endothelial cells (HUVECs) to determine cytotoxicity and pro-inflammatory stimulus capacity. We found that ZS-Ag-NPs treated adipocyte CM effectively increased mRNA expression levels of the vascular endothelial cell growth factor (VEGF), and down-regulated oxidative stress (LPO, eNOS, and HO) and vascular cell inflammation (ICAM, VCAM, TNF-α, IL-1β, and NF-κB). In conclusion, ZS-Ag-NPs displayed an action at the molecular level in mitochondrial fatty acid oxidation, decreased adipokine secretion in adipocytes, and enhanced vascular endothelial cell growth. This molecular mechanical action of ZS-Ag-NPs reduced effectively obesity progressions and metabolic inflammatory pathogenesis associated with aging.

Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports.

Recently, several studies have highlighted the tight connection between mitochondria and physical activity. Mitochondrial functions are important in high-demanding metabolic activities, such as endurance sports. Moreover, regular training positively affects metabolic health by increasing mitochondrial oxidative capacity and regulating glucose metabolism. Exercise could have multiple effects, also on the mitochondrial DNA (mtDNA) and vice versa; some studies have investigated how mtDNA polymorphisms can affect the performance of general athletes and mtDNA haplogroups seem to be related to the performance of elite endurance athletes. Along with several stimuli, including pathogens, stress, trauma, and reactive oxygen species, acute and intense exercise also seem to be responsible for mtDNA release into the cytoplasm and extracellular space, leading to the activation of the innate immune response. In addition, several sports are characterized by a higher frequency of injuries, including cranial trauma, associated with neurological consequences. However, with regular exercise, circulating cell-free mtDNA levels are kept low, perhaps promoting cf-mtDNA removal, acting as a protective factor against inflammation.

Mitochondrial Oxidation of the Cytoplasmic Reducing Equivalents at the Onset of Oxidant Stress in the Isoproterenol-Induced Rat Myocardial Infarction.

We have developed and characterized a model of isoproterenol (ISO)-induced myocardial necrosis, identifying three stages of cardiac damage: a pre-infarction (0–12 h), infarction (24 h), and post-infarction period (48–96 h). Using this model, we have previously found alterations in calcium homeostasis and their relationship with oxidant stress in mitochondria, which showed deficient oxygen consumption and coupled ATP synthesis. Therefore, the present study was aimed at assessing the mitochondrial ability to transport and oxidize cytoplasmic reducing equivalents (NADH), correlating the kinetic parameters of the malate-aspartate shuttle, oxidant stress, and mitochondrial functionality. Our results showed only discreet effects during the cardiotoxic ISO action on the endogenous malate-aspartate shuttle activity, suggesting that endogenous mitochondrial NADH oxidation capacity (Nohl dehydrogenase) was not affected by the cellular stress. On the contrary, the reconstituted system showed significant enhancement in maximal capacity of the malate-aspartate shuttle activity only at later times (post-infarction period), probably as a compensatory part of cardiomyocytes’ response to the metabolic and functional consequences of the infarcted tissue. Therefore, these findings support the notion that heart damage associated with myocardial infarction suffers a set of sequential biochemical and metabolic modifications within cardiomyocytes, where mitochondrial activity, controlling the redox state, could play a relevant role.

Abstract 113: Targeting Receptor-interacting Protein 140 (RIP140) To Modulate Energy Metabolism In The Failing Heart

During the development of heart failure (HF), the PPAR/ERR complex becomes deactivated resulting in diminished capacity for mitochondrial fatty acid oxidation (FAO) and ATP production leading to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PPAR/ERR in some extra-cardiac tissues. We hypothesized that inhibition of RIP140 would re-activate PPAR/ERR enhancing capacity for fuel catabolism and ATP production in the failing heart. Heart and skeletal muscle-specific RIP140 knockout mice (strRIP140KO) were resistant to the development of cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload that mimicked features of HF with preserved ejection fraction (HFpEF). To further evaluate the role of RIP140 in heart, cardiac-specific (cs) RIP140KO mice were generated. 13 C-substrate NMR studies demonstrated that palmitate oxidation and triglyceride turnover rates were significantly accelerated in isolated perfused csRIP140KO hearts. csRIP140KO were subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), to produce HF with reduced EF (HFrEF). Compared to controls, csRIP140KO exhibited reduced left ventricular remodeling and systolic dysfunction when subjected to TAC/MI. RNA-sequence analysis demonstrated that many genes involved in FAO, branched-chain amino acid catabolism, oxidative phosphorylation, and adult muscle contraction programs were significantly “protected” (less downregulation) by RIP140 deletion in the context of TAC/MI. To identify candidate cardiac RIP140 targets, “CUT&amp;RUN”-sequencing was conducted on cardiomyocytes (CM) from csRIP140KO and controls to identify changes in enhancer regions. Motif analysis of peaks with increased H3K27ac deposition in the csRIP140KO CM identified ERR, PPAR, myocyte enhancer 2 (MEF2), glucocorticoid receptor (GR), and kruppel-like factor (KLF) binding sites. We conclude that RIP140 serves as a global co-repressor of a network of transcription factors that control cardiac energy metabolic and contractile function, and that inhibition of RIP140 could prove to be a novel therapeutic approach for HF.

Lower extremity MRI following 10-week supervised exercise intervention in patients with diabetic peripheral neuropathy

IntroductionThe purpose of this study was to characterize using MRI the effects of a 10-week supervised exercise program on lower extremity skeletal muscle composition, nerve microarchitecture, and metabolic function in...

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model.

ABSTRACTMitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.

Effect of the MPT Pore Inhibitor Alisporivir on the Development of Mitochondrial Dysfunction in the Heart Tissue of Diabetic Mice.

Simple SummaryDiabetes mellitus as a systemic metabolic disease is one of the most serious threats to global health in this century. Diabetic cardiomyopathy is increasingly recognized as one of the most important complications of the disease, which is associated with impaired cell energy metabolism and damage to mitochondria in cardiomyocytes. Therefore, targeting mitochondrial dysfunction by pharmacological agents can be used as a therapeutic strategy in diabetic heart disease. The aim of the work was to study the effect of the mitochondria-targeted agent alisporivir on the development of mitochondrial dysfunction in the heart of mice with experimental diabetes mellitus. Alisporivir has been recently identified as a non-immunosuppressive analogue of cyclosporin A, a selective inhibitor of cyclophilin D and the mitochondrial permeability transition pore opening, with a potential in a wide range of therapeutic indications. Our results indicated that alisporivir alleviates diabetes-induced abnormalities in the ultrastructure and functions of mitochondria in cardiomyocytes and increases the rate of glucose utilization in diabetic mice. The data suggest that alisporivir acts as a mitochondria-targeted metabolic reprogramming agent and attenuates oxidative damage to the heart tissue of diabetic mice.Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with the mitochondrial permeability transition (MPT) pore opening being considered as one of its possible mechanisms. The effect of alisporivir, a non-immunosuppressive cyclosporin derivative and a selective inhibitor of the MPT pore opening, on the ultrastructure and functions of the heart mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections was studied. The treatment of diabetic animals with alisporivir (2.5 mg/kg ip for 20 days) increased the rate of glucose clearance during the glucose tolerance test. The blood glucose level and the indicator of heart rate in alisporivir-treated diabetic mice tended to restore. An electron microscopy analysis showed that alisporivir prevented mitochondrial swelling and ultrastructural alterations in cardiomyocytes of diabetic mice. Alisporivir canceled the diabetes-induced increases in the susceptibility of heart mitochondria to the MPT pore opening and the level of lipid peroxidation products, but it did not affect the decline in mitochondrial oxidative phosphorylation capacity. The mRNA expression levels of Pink1 and Parkin in the heart tissue of alisporivir-treated diabetic mice were elevated, suggesting the stimulation of mitophagy. In parallel, alisporivir decreased the level of mtDNA in the heart tissue. These findings suggest that targeting the MPT pore opening by alisporivir alleviates the development of mitochondrial dysfunction in the diabetic heart. The cardioprotective effect of the drug in diabetes can be mediated by the induction of mitophagy and the inhibition of lipid peroxidation in the organelles.

Requirements for successful mitochondrial transplantation.

Maintenance of mitochondrial oxidative phosphorylation capacity and other mitochondrial functions are essential for the prevention of mitochondrial dysfunction-related diseases such as neurodegenerative, cardiovascular, and liver diseases. To date, no well-known treatment modality has been developed to prevent or reduce mitochondrial dysfunction. However, a novel approach that transplants fully functional mitochondria directly into defective cells has recently caught the attention of scientists. In this review, we provide an overview of the cell/tissue source of the mitochondria to prompt cell regeneration or tissue repair in vitro and in vivo applications. The animal and human models entail that effective procedures should be used in the isolation and confirmation of mitochondrial membrane potential and function. We believe that these procedures for mitochondrial transplantation for tissue or cell culture will confirm intact, viable, and free from contamination isolated mitochondria from the appropriate sources.

Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes

In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether proteins located at MAMs could play a key role in preventing triglyceride accumulation in hepatocytes and nonalcoholic fatty liver disease (NAFLD) occurrence. To test this, we explored the role of two key partners in building MAM integrity and functionality, the glucose-regulated protein 75 (Grp75) and mitofusin 2 (Mfn2), which liver contents are altered in obesity and NAFLD. Grp75 or Mfn2 expression was either silenced using siRNA or overexpressed with adenoviruses in Huh7 cells.Silencing of Grp75 and Mfn2 resulted in decreased ER-mitochondria interactions, mitochondrial network fusion state and mitochondrial oxidative capacity, while overexpression of the two proteins induced mirror impacts on these parameters. Furthermore, Grp75 or Mfn2 silencing decreased cellular cholesterol content and enhanced triglyceride secretion in ApoB100 lipoproteins, while their overexpression led to reverse effects. Cellular phosphatidylcholine/phosphatidylethanolamine ratio was decreased only upon overexpression of the proteins, potentially contributing to altered ApoB100 assembly and secretion. Despite the opposite differences, both silencing and overexpression of Grp75 or Mfn2 induced triglyceride storage, although a fatty acid challenge was required to express the alteration upon protein silencing. Among the mechanisms potentially involved in this phenotype, ER stress was closely associated with altered triglyceride metabolism after Grp75 or Mfn2 overexpression, while blunted mitochondrial FA oxidation capacity may be the main defect causing triglyceride accumulation upon Grp75 or Mfn2 silencing. Further studies are required to decipher the link between modulation of Grp75 or Mfn2 expression, change in MAM integrity and alteration of cholesterol content of the cell.In conclusion, Grp75 or Mfn2 silencing and overexpression in Huh7 cells contribute to altering MAM integrity and cholesterol storage in opposite directions, but all promote triglyceride accumulation through distinct cellular pathways. This study also highlights that besides Mfn2, Grp75 could play a central role in hepatic lipid and cholesterol metabolism in obesity and NAFLD.

Analytical Determination of Mitochondrial Function of Excised Solid Tumor Homogenates

We developed a practical protocol and analytical approach to evaluate mitochondrial oxidative phosphorylation and electron transfer capacity in fresh tumor homogenates. This protocol can be easily adapted to survey various mitochondrial functions that contribute to cancer initiation, progression, and treatment response.

Revisiting the limitation to with ageing: is mitochondrial (dys)function the key?

Revisiting the limitation to with ageing: is mitochondrial (dys)function the key?

Under the Hood: Skeletal Muscle Determinants of Endurance Performance.

In the past decades, researchers have extensively studied (elite) athletes' physiological responses to understand how to maximize their endurance performance. In endurance sports, whole-body measurements such as the maximal oxygen consumption, lactate threshold, and efficiency/economy play a key role in performance. Although these determinants are known to interact, it has also been demonstrated that athletes rarely excel in all three. The leading question is how athletes reach exceptional values in one or all of these determinants to optimize their endurance performance, and how such performance can be explained by (combinations of) underlying physiological determinants. In this review, we advance on Joyner and Coyle's conceptual framework of endurance performance, by integrating a meta-analysis of the interrelationships, and corresponding effect sizes between endurance performance and its key physiological determinants at the macroscopic (whole-body) and the microscopic level (muscle tissue, i.e., muscle fiber oxidative capacity, oxygen supply, muscle fiber size, and fiber type). Moreover, we discuss how these physiological determinants can be improved by training and what potential physiological challenges endurance athletes may face when trying to maximize their performance. This review highlights that integrative assessment of skeletal muscle determinants points toward efficient type-I fibers with a high mitochondrial oxidative capacity and strongly encourages well-adjusted capillarization and myoglobin concentrations to accommodate the required oxygen flux during endurance performance, especially in large muscle fibers. Optimisation of endurance performance requires careful design of training interventions that fine tune modulation of exercise intensity, frequency and duration, and particularly periodisation with respect to the skeletal muscle determinants.

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice.

The central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previously, increased acute food intake following the chemical reduction of hepatic fatty acid oxidation and ATP levels was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a hepatocyte PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male, but not female, mice had a 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain compared to wildtype (WT) mice (p < 0.05). The greater weight gain was associated with altered feeding behavior and lower activity energy expenditure during the HFHS diet in LPGC1a males. WT and LPGC1a mice underwent sham surgery or HBV to assess whether vagal signaling was involved in the HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p < 0.05) in male WT mice, but not LPGC1a mice. These data demonstrate a sex-specific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need for a more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.

Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests.

The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has become the most frequent type of chronic liver disorder with risk of progression to cirrhosis and hepatocellular carcinoma. Liver mitochondria play a key role in degrading the pathways of carbohydrates, proteins, lipids, and xenobiotics, and to provide energy for the body cells. The morphological and functional integrity of mitochondria guarantee the proper functioning of β-oxidation of free fatty acids and of the tricarboxylic acid cycle. Evaluation of the liver in clinical medicine needs to be accurate in NAFLD patients and includes history, physical exam, imaging, and laboratory assays. Evaluation of mitochondrial function in chronic liver disease and NAFLD is now possible by novel diagnostic tools. “Dynamic” liver function tests include the breath test (BT) based on the use of substrates marked with the non-radioactive, naturally occurring stable isotope 13C. Hepatocellular metabolization of the substrate will generate 13CO2, which is excreted in breath and measured by mass spectrometry or infrared spectroscopy. Breath levels of 13CO2 are biomarkers of specific metabolic processes occurring in the hepatocyte cytosol, microsomes, and mitochondria. 13C-BTs explore distinct chronic liver diseases including simple liver steatosis, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, hepatocellular carcinoma, drug, and alcohol effects. In NAFLD, 13C-BT use substrates such as α-ketoisocaproic acid, methionine, and octanoic acid to assess mitochondrial oxidation capacity which can be impaired at an early stage of disease. 13C-BTs represent an indirect, cost-effective, and easy method to evaluate dynamic liver function. Further applications are expected in clinical medicine. In this review, we discuss the involvement of liver mitochondria in the progression of NAFLD, together with the role of 13C-BT in assessing mitochondrial function and its potential use in the prevention and management of NAFLD.

Lactate Fluxes and Plasticity of Adipose Tissues: A Redox Perspective.

Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging.