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Chronic intrauterine hypoxia is a significant pregnancy complication impacting fetal heart growth, metabolism, and mitochondrial function, contributing to cardiovascular programming of the offspring. PGC1α (peroxisome proliferator-activated receptor γ co-activator 1α) is the master regulator of mitochondrial biogenesis. We investigated the effects of hypoxia on PGC1α expression following exposure at different gestational ages. Time-mated pregnant guinea pigs were exposed to normoxia (NMX, 21% O 2 ) or hypoxia (HPX, 10.5% O 2 ) at either 25-day (early-onset) or 50-day (late-onset) gestation, and all fetuses were extracted at term (term = ~65-day gestation). Expression of nuclear PGC1α, sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and mitochondrial sirtuin 3 (SIRT3) was measured, along with SIRT3 activity and mitochondrial acetylation of heart ventricles of male and female fetuses. Early-onset hypoxia increased (P<0.05) fetal cardiac nuclear PGC1α and had no effect on mitochondrial acetylation of either growth-restricted males or females. Late-onset hypoxia had either no effect or decreased (P<0.05) PCC1α expression in males and females, respectively, but increased (P<0.05) mitochondrial acetylation in both sexes. Hypoxia had variable effects on expression of SIRT1, AMPK, SIRT3, and SIRT3 activity depending on the sex. The capacity of the fetal heart to respond to hypoxia differs depending on the gestational age of exposure and sex of the fetus. Further, the effects of late-onset hypoxia on fetal heart function impose a greater risk to male than female fetuses, which has implications toward cardiovascular programming effects of the offspring., (© 2023. The Author(s).)

Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.

Chronic heart failure (CHF), the new epidemic in cardiology, is characterized by energetic failure of both cardiac and skeletal muscles. The failing heart wastes energy due to anatomical changes that include cavity enlargement, altered geometry, tachycardia, mitral insufficiency and abnormal loading, while skeletal muscle undergoes atrophy. Cardiac and skeletal muscles also have altered high-energy phosphate production and handling in CHF. Nevertheless, there are differences in the phenotype of myocardial and skeletal muscle myopathy in CHF: cardiomyocytes have a lower mitochondrial oxidative capacity, abnormal substrate utilisation and intracellular signalling but a maintained oxidative profile; in skeletal muscle, by contrast, mitochondrial failure is less clear, and there is altered microvascular reactivity, fibre type shifts and abnormalities in the enzymatic systems involved in energy distribution. Underlying these phenotypic abnormalities are changes in gene regulation in both cardiac and skeletal muscle cells. Here, we review the latest advances in cardiac and skeletal muscle energetic research and argue that energetic failure could be taken as a unifying mechanism leading to contractile failure, ultimately resulting in skeletal muscle energetic failure, exertional fatigue and death.

Techniques and protocols of assessment of mitochondrial properties are of physiological and physiopathological important significance. A precise knowledge of the advantages and limitations of the different protocols used to investigate the mitochondrial function, is therefore necessary. This report presents examples of how the skinned (or permeabilized) fibers technique could be applied for the polarographic determination of the actual quantitative and qualitative aspects of mitochondrial function in human muscle samples. We described and compared the main available respiration protocols in order to sort out which protocol seems more appropriate for the characterization of mitochondrial properties according to the questions under consideration: quantitative determination of oxidative capacities of a given muscle, characterization of the pattern of control of mitochondrial respiration, or assessment of a mitochondrial defect at the level of the respiratory chain complexes. We showed that while protocol A, using only two levels of the phosphate acceptor adenosine diphosphate (ADP) concentration and the adjunction of creatine, could be used for the determination of quantitative changes in very small amount of muscle samples, the ADP sensitivity of mitochondrial respiration was underestimated by this protocol in muscles with high oxidative capacities. The actual apparent Km for ADP and the role of functional activation of miCK in ATP production and energy transfer in oxidative muscles, are well-assessed by protocol B (in the absence of creatine) together with protocol C (in the presence of creatine) that use increasing concentrations of ADP ranging from 2.5-2000 microM. Protocol D is well-adapted to investigate the potential changes at different levels of the respiratory chain, by the use of specific substrates and inhibitors. As can be seen from the present data and the current review of previous reports in the literature, a standardization of the respiration protocols is needed for useful comparisons between studies.

In adult mammalian muscle cells, energy consuming processes are mainly localized to the sarcolemma, sarcoplasmic reticulum (SR) and myofibrillar compartments, while energy production occurs within mitochondria or glycolytic complexes. Due to the restricted diffusion of adenine nucleotides near the active sites of ATPases involved in contractile activity and calcium homeostasis, there are multiple local systems that can locally rephosphorylate ADP and provide ATP. The creatine kinase (CK) system, with specific isoenzymes localized within each compartment, efficiently controls local adenylate pools and links energy production and utilization. However, mice lacking one or both of the MM-CK and mi-CK isoforms (CK-/-) are viable and develop almost normal cardiac and skeletal muscle function under the conditions of moderate workload, suggesting adaptations or other mechanisms that may ensure efficient energy transfer. While fixed CK is essentially important, other systems could also be involved as well, such as bound glycolytic enzymes or adenylate kinase. We have shown that, additionally, a direct functional interplay exists between mitochondria and sarcoplasmic reticulum, or between mitochondria and myofilaments in muscle cells, that catalyzes direct energy and signal transfer between organelles. In cardiac cells of CK-/- mice, marked cytoarchitectural modifications were observed, and direct adenine nucleotide channeling between mitochondria and organelles was very effective to rescue SR and myofilament functions. In fast skeletal muscles, increased oxidative capacity also indicates compensatory mechanisms. In mutant mice, mitochondrial capacity increases and a direct energy channeling occurs between mitochondria on one hand and ATP consuming sites on the other. However, these systems appear to be insufficient to fully compensate for the lack of CK at high workload. It can be concluded that local rephosphorylation of ADP is a crucial regulatory point in highly differentiated and organized muscle cells to ensure contractile diversity and efficiency and that the CK system is important to control energy fluxes and energy homeostasis.

Cytoskeletal reorganization has been shown to participate in cellular remodeling and in the alterations of mechanical function of isolated cardiomyocytes during pressure overload hypertrophy. Post-translational modifications of tubulin towards stabilization of microtubules have also been described in animal models of compensatory hypertrophy, but the status of the microtubules network in end stage heart failure is not clearly established. Using a rat model of congestive heart failure (CHF) induced by aortic banding, we studied the expression of alpha- and beta-tubulin, as well as their post-translational modification and distribution in the soluble and polymerized fraction by immunoblotting. We found an accumulation of alpha- and beta-tubulin protein content specifically in the soluble fraction with no change in the polymerized fraction. Amongst the several variants of alpha-tubulin examined, only detyrosinated Glu-tubulin and deglutamylated delta2-tubulin levels were selectively increased during heart failure. Glu-tubulin accumulated in the polymerized fraction while delta2-tubulin levels were increased in the soluble fraction in CHF hearts. These results show that a profound remodeling of the microtubule network occurs in heart failure. This remodeling suggests an increase in the stability of the microtubule network which is discussed in terms of possible functional consequences.

In saponin-skinned muscle fibers from adult rat heart and m. soleus the apparent affinity of the mitochondrial oxidative phosphorylation system for ADP (Km = 200-400 microM) is much lower than in isolated mitochondria (Km = 10-20 microM). This suggests a limited permeability of the outer mitochondrial membrane (OMM) to adenine nucleotides in slow-twitch muscle cells. We have studied the postnatal changes in the affinity of mitochondrial respiration for ADP, in relation to morphological alterations and expression of mitochondrial creatine kinase (mi-CK) in rat heart in vivo. Analysis of respiration of skinned fibers revealed a gradual decrease in the apparent affinity of mitochondria to ADP throughout 6 weeks post partum that indicates the development of mechanism which increasingly limits the access of ADP to mitochondria. The expression of mi-CK started between the 1st and 2nd weeks and reached the adult levels after 6 weeks. This process was associated with increases in creatine-activated respiration and affinity of oxidative phosphorylation to ADP thus reflecting the progressive coupling of mi-CK to adenine nucleotide translocase. Laser confocal microscopy revealed significant changes in rearrangement of mitochondria in cardiac cells: while the mitochondria of variable shape and size appeared to be random-clustered in the cardiomyocytes of 1 day old rat, they formed a fine network between the myofibrils by the age of 3 weeks. These results allow to conclude that in early period of development, i.e. within 2-3 weeks, the diffusion of ADP to mitochondria becomes progressively restricted, that appears to be related to significant structural rearrangements such as formation of the mitochondrial network. Later (after 3 weeks) the control shifts to mi-CK, which by coupling to adenine nucleotide translocase, allows to maximally activate the processes of oxidative phosphorylation despite limited access of ADP through the OMM.

Creatine kinase (CK) isoenzymes are present in all vertebrates. An important property of the creatine kinase system is that its total activity, its isoform distribution, and the concentration of guanidino substrates are highly variable among species and tissues. In the highly organized structure of adult muscles, it has been shown that specific CK isoenzymes are bound to intracellular compartments, and are functionally coupled to enzymes and transport systems involved in energy production and utilization. It is however, not established whether functional coupling and intracellular compartmentation are present in all vertebrates. Furthermore, these characteristics seem to be different among different muscle types within a given species. This study will review some of these aspects. It has been observed that: (1) In heart ventricle, CK compartmentation and coupling characterize adult mammalian cells. It is almost absent in frogs, and is weakly present in birds. (2) Efficient coupling of MM-CK to myosin ATPase is seen in adult mammalian striated muscles but not in frog and bird heart where B-CK is expressed instead of M-CK. Thus, the functional efficacy of bound MM-CK to regulate adenine nucleotide turnover within the myofibrillar compartment seems to be specific for muscles expressing M-CK as an integral part of the sarcomere. (3) Mi-CK expression and/or functional coupling are highly tissue and species specific; moreover, they are subject to short term and long term adaptations, and are present late in development. The mitochondrial form of CK (mi-CK) can function in two modes depending on the tissue: (i) in an <> and (ii) in an <>. The mode of action of mi-CK seems to be related to its precise localization within the mitochondrial intermembrane space, whereas its amount might control the quantitative aspects of the coupling. Mi-CK is highly plastic, making it a strong candidate for fine regulation of excitation-contraction coupling in muscles and for energy transfer in cells with large and fluctuating energy demands in general. (4) Although CK isoforms show a binding specificity, the presence of a given isoform within a tissue or a species only, does not predict its functional role. For example, M-CK is expressed before it is functionally compartmentalized within myofibrils during development. Similarly, the presence of ubiquitous or sarcomeric mi-CK isoforms, is not an index of functional coupling of mi-CK to oxidative phosphorylation. (5) Amongst species or muscles, it appears that a large buffering action of the CK system is associated with rapid contraction and high glycolytic activity. On the other hand, an oxidative metabolism is associated with isoform diversity, increased compartmentation, a subsequent low buffering action and efficient phosphotransfer between mitochondria and energy utilization sites. It can be concluded that, in addition to a high variation of total activity and isoform expression, the role of the CK system also critically depends on its intracellular organization and interaction with energy producing and utilizing pathways. This compartmentation will determine the high cellular efficiency and fine specialization of highly organized and differentiated muscle cells.

The role of creatine kinase (CK) bound to sarcoplasmic reticulum (SR), in the energy supply of SR ATPase in situ, was studied in saponin-permeabilised rat ventricular fibres by loading SR at pCa 6. 5 for different times and under different energy supply conditions. Release of Ca2+ was induced by 5 mM caffeine and the peak of relative tension (T/Tmax) and the area under isometric tension curves, ST, were measured. Taking advantage of close localisation of myofibrils and SR, free [Ca2+] in the fibres during the release was estimated using steady state [Ca2+]/tension relationship. Peak [Ca2+] and integral of free Ca2+ transients (S[Ca2+]f) were then calculated. At all times, loading with 0.25 mM adenosine diphosphate, Mg2+ salt (MgADP) and 12 mM phosphocreatine (PCr) [when adenosine triphosphate (ATP) was generated via bound CK] was as efficient as loading with both 3.16 mM MgATP and 12 mM PCr (control conditions). However, when loading was supported by MgATP alone (3.16 mM), T/Tmax was only 40% and S[Ca2+]f 31% of control (P < 0.001). Under these conditions, addition of a soluble ATP-regenerating system (pyruvate kinase and phosphoenolpyruvate), did not increase loading substantially. Both ST and S[Ca2+]f were more sensitive to the loading conditions than T/Tmax and peak [Ca2+]. The data suggest that Ca2+ uptake by the SR in situ depends on local ATP/ADP ratio which is effectively controlled by bound CK.

Very recent experimental data, obtained by using the permeabilized cell technique or tissue homogenates for investigation of the mechanisms of regulation of respiration in the cells in vivo, are shortly summarized. In these studies, surprisingly high values of apparent Km for ADP, exceeding that for isolated mitochondria in vitro by more than order of magnitude, were recorded for heart, slow twitch skeletal muscle, hepatocytes, brain tissue homogenates but not for fast twitch skeletal muscle. Mitochondrial swelling in the hypo-osmotic medium resulted in the sharp decrease of the value of Km for ADP in correlation with the degree of rupture of mitochondrial outer membrane, as determined by the cytochrome c test. Very similar effect was observed when trypsin was used for treatment of skinned fibers, permeabilized cells or homogenates. It is concluded that, in many but not all types of cells, the permeability of the mitochondria outer membrane for ADP is controlled by some cytoplasmic protein factor(s). Since colchicine and taxol were not found to change high values of the apparent Km for ADP, the participation of microtubular system seems to be excluded in this kind of control or respiration but studies of the roles of other cytoskeletal structures seem to be of high interest. In acute ischemia we observed rapid increase of the permeability of the mitochondrial outer membrane for ADP due to mitochondrial swelling and concomitant loss of creatine control of respiration as a result of dissociation of creatine kinase from the inner mitochondrial membrane. The extent of these damages was decreased by use of proper procedures of myocardial protection showing that outer mitochondrial membrane permeability and creatine control of respiration are valuable indices of myocardial preservation. In contrast to acute ischemia, chronic hypoxia seems to improve the cardiac cell energetics as seen from better postischemic recovery of phosphocreatine, and phosphocreatine overshoot after inotropic stimulation. In general, adaptational possibilities and pathophysiological changes in the mitochondrial outer membrane system point to the central role such a system may play in regulation of cellular energetics in vivo.

Maturation of the cardiac cell is characterized by increasing diversity of isozymic expression of creatine kinases. Expression of the M-CK isozyme always precedes that of mitochondrial isozyme (mi-CK), however the expression of an isoform does not inform about its localization or cellular function. The functional role of isozymes binding to sites of energy utilization and production characteristic of the adult myocardium can be evidenced by the functional coupling of M-CK to myofibrillar ATPase and mito-CK to translocase in Triton X-100 and saponin skinned fibers. Functional activity of M-CK and mito-CK were investigated during perinatal development. Both functional activities appear during late fetal life in species mature at birth like guinea pig, and in the first postnatal weeks in immature species like rat or rabbit. Thus, the functional activity of bound CK isozymes is not associated with birth per se but with the general process of cell maturation. Localization of CK in the cytosol appears optimal for the transfer of glycolytic production of ATP to sites of utilization in an immature heart. During cell maturation, the increasing contribution of oxidative phosphorylation to ATP production, the apparition and binding of mi-CK to mitochondria, the binding of M-CK to myofibrils, turn the cell in a compartmentalized system of energy production. This provides the cellular basis for energy transfer by the PCr-Cr-CK system between sites of ATP production and utilization. Compartmentation of both Ca handling and energy turnover leads to a highly structured cell organization and could be essential for the efficiency of heart function.

This article is a review on the organization and function of myofibrillar creatine kinase in striated muscle. The first part describes myofibrillar creatine kinase as an integral structural part of the complex organization of myofibrils in striated muscle. The second part considers the intrinsic biochemical and mechanical properties of myofibrils and the functional coupling between myofibrillar CK and myosin ATPase. Skinned fiber studies have been developed to evidence this functional coupling and the consequences for cardiac contraction. The data show that creatine kinase in myofibrils is effective enough to sustain normal tension and relaxation, normal Ca sensitivity and kinetic characteristics. Moreover, the results suggest that myofibrillar creatine kinase is essential in maintaining adequate ATP/ADP ratio in the vicinity of myosin ATPase active site to prevent dysfunctioning of this enzyme. Implications for the physiology and physiopathology of cardiac muscle are discussed.

Human cardiomyopathy has been extensively studied in the last decade, and knowledge of the functional and structural alterations of the heart has grown. However, understanding of the pathogenesis has come mostly from experimental studies. A number of work have been designed to elucidate if alterations of the contractile apparatus of cardiac cells contribute to the impairment of heart mechanics in cardiomyopathies. As well, an important question is to be solved: whether energy supply of the contraction-relaxation cycle is sufficient in the myopathic heart. Use of cardiac fibers skinned by different techniques allows to evaluate functional ability of myofibrils, mitochondria and bound creatine kinase which plays an important role in cardiomyocyte energy metabolism. The data presented in this chapter show that experimental cardiomyopathies of various types have some common features. These are an increase in calcium sensitivity of myofibrils and a depression of functional activity of mitochondrial creatine kinase. Possible mechanisms and physiological significance of these changes are discussed.

Pulmonary hypertension (PH) is heterogeneous diseases that can lead to death due to progressive right heart failure. Emerging evidence suggests that, in addition to its role in ATP production, changes in mitochondrial play a central role in their pathogenesis, regulating integrated metabolic and signal transduction pathways. This review focuses on the basic principles of mitochondrial redox status in pulmonary vascular and right ventricular disorders, a series of dysfunctional processes including mitochondrial quality control (mitochondrial biogenesis, mitophagy, mitochondrial dynamics, mitochondrial unfolded protein response) and mitochondrial redox homeostasis. In addition, we will summarize how mitochondrial renewal and dynamic changes provide innovative insights for studying and evaluating PH. This will provide us with a clearer understanding of the initial signal transmission of mitochondria in PH, which would further improve our understanding of the pathogenesis of PH., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the absence of creatine phosphate, MgATP produced relaxation of rigor tension in chemically-skinned right papillary muscles of the rat, the half maximal effect being obtained at 1.8 mM MgATP. In the presence of 12 mM creatine phosphate and 250 microM ADP, a decrease in MgATP concentration even to 10(-9) M never induced rigor tension. At a very low MgATP concentration (10(-6) M), the half maximal relaxing effect was obtained with 2 mM creatine phosphate, a value close to the Km of isolated MM-creatine kinase for this substrate, or with 14 microM MgADP, a value 5 times lower than the reported Km. An exogenous MgATP regenerating system (phosphoenol pyruvate + pyruvate kinase) was not able to fully relax the fibres. When MM-creatine kinase was inhibited by fluorodinitrobenzene, the dependency of rigor tension on MgATP became the same as it was without creatine phosphate. After washing out the fluorodinitrobenzene the addition of exogenous MM-creatine kinase for half an hour fully relaxed rigor tension; moreover, this effect persisted even after prolonged washout. These results show that endogenous MM-creatine kinase is able to ensure maximal efficiency of myosin ATPase by producing a localized high MgATP/MgADP ratio; they also suggest the existence of rapidly exchangeable binding sites for MM-creatine kinase in cardiac myofibrils.

The effects of inorganic phosphate (Pi) on mechanical properties of Triton X100 treated ventricular fibres have been studied in different substrate conditions. In the presence of both MgATP and phosphocreatine, increasing concentrations of Pi progressively decreased maximal active force, up to 50-60% at 20 mM Pi. The reduction in stiffness was slightly less. These effects appeared nearly independent of the diameter of the preparations. 20 mM Pi decreased Ca sensitivity of the myofilaments and increased the Hill coefficient of the tension/pCa relationship; furthermore, the time constant of tension recovery was decreased from 12.9 to 8.9 ms suggesting that the cycling rate of cross-bridges was increased in the presence of Pi. When MgATP was regenerated by the myofilament bound creatine kinase in the presence of phosphocreatine, Pi was less efficient in decreasing the maximal tension and it weakened the relaxing effect of MgATP upon rigor tension. These effects are related to the inhibition of creatine kinase by Pi. The effects of Pi on maximal force and kinetics of contraction were antagonized by the effects of a decrease in phosphocreatine. The results are discussed in terms of the antagonistic role of Pi increase and phosphocreatine decrease upon contractile properties of myofilaments during hypoxia in heart muscle.

Mitochondrial protein sequence similarity 3 gene family member A (FAM3A) plays important roles in the electron transfer chain, while its functions in the heart are still unknown. This study aims to explore the roles and mechanisms of FAM3A after myocardial infarction (MI). FAM3A-deficient (Fam3a -/- ) mice were implemented with MI injury and showed lower survival rates at 4 weeks as well as decreased cardiac systolic function. Isolated cardiomyocytes of Fam3a -/- mice showed reduced basal, ATP-linked respiration and respiratory reserve compared to that of wild-type mice. Transmission electron microscopy studies showed Fam3a -/- mice had a larger size and elevated density of mitochondria. FAM3A deficiency also induced elevated mitochondrial Ca 2+ , higher opening level of mPTP, lower mitochondrial membrane potential and elevated apoptotic rates. Further analyses demonstrated that mitochondrial dynamics protein Opa1 contributed to the effects of FAM3A in cardiomyocytes. Our study discloses the important roles of mitochondrial protein FAM3A in the heart., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cardiovascular diseases (CVD) account for the largest bulk of deaths worldwide, posing a massive burden on societies and the global healthcare system. Besides, the incidence and prevalence of these diseases are on the rise, demanding imminent action to revert this trend. Cardiovascular pathogenesis harbors a variety of molecular and cellular mechanisms among which dysregulated metabolism is of significant importance and may even proceed other mechanisms. The healthy heart metabolism primarily relies on fatty acids for the ultimate production of energy through oxidative phosphorylation in mitochondria. Other metabolites such as glucose, amino acids, and ketone bodies come next. Under pathological conditions, there is a shift in metabolic pathways and the preference of metabolites, termed metabolic remodeling or reprogramming. In this review, we aim to summarize cardiovascular metabolism and remodeling in different subsets of CVD to come up with a new paradigm for understanding and treatment of these diseases., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The heart is the most energy-demanding organ throughout the whole body. Perturbations or failure in energy metabolism contributes to heart failure (HF), which represents the advanced stage of various heart diseases. The poor prognosis and huge economic burden associated with HF underscore the high unmet need to explore novel therapies targeting metabolic modulators beyond conventional approaches focused on neurohormonal and hemodynamic regulators. Emerging evidence suggests that alterations in metabolic substrate reliance, metabolic pathways, metabolic by-products, and energy production collectively regulate the occurrence and progression of HF. In this review, we provide an overview of cardiac metabolic remodeling, encompassing the utilization of free fatty acids, glucose metabolism, ketone bodies, and branched-chain amino acids both in the physiological condition and heart failure. Most importantly, the latest advances in pharmacological interventions are discussed as a promising therapeutic approach to restore cardiac function, drawing insights from recent basic research, preclinical and clinical studies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The etiology of peripartum cardiomyopathy (PPCM) is unknown. Therefore, we evaluated the etiology of patients clinically diagnosed with PPCM using endomyocardial biopsy. We studied five patients diagnosed with PPCM following endomyocardial biopsy (age, 28-42 years; mean age, 35 years). Biopsied samples were evaluated using microscopy, including immunostaining and electron microscopy. The pathological findings were as follows: myocardial hypertrophy, myocardial fibrosis, and cell infiltration. Two patients were diagnosed with lymphocytic myocarditis, one with eosinophilic myocarditis, one with hypertensive heart disease, and one with a combination of hypertension and myocarditis. Endomyocardial biopsy suggested that the causes of PPCM were varied and related to myocarditis and myocardial overload due to hypertension., (© 2022. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Mitochondrial dysfunction is a fundamental mechanism leading to drug nephrotoxicity, such as gentamicin-induced nephrotoxicity. Mitochondrial therapy (mitotherapy) or exogenous mitochondria transplantation is a method that can be used to replace dysfunctional mitochondria with healthy mitochondria. This method can help in the treatment of diseases related to mitochondria. In this research, we studied the transplantation effect of freshly isolated mitochondria on the toxicity induced by gentamicin on renal proximal tubular cells (RPTCs). Furthermore, possible gender-related effects on supplying exogenous rat kidney mitochondria on gentamicin-induced RPTCs were investigated. At first, the normality and proper functioning of fresh mitochondria were assessed by measuring mitochondrial succinate dehydrogenase activity (SDH) and changes in mitochondrial membrane potential (MMP). Then, the protective effects of mitochondrial transplantation against gentamicin-induced mitochondrial toxicity were evaluated through parameters including lactate dehydrogenase (LDH) leakiness, reactive oxygen species (ROS) production, lipid peroxidation (LPO) content, reduced glutathione (GSH) level, extracellular oxidized glutathione (GSSG) level, ATP level, MMP collapse, and caspase-3 activity. According to the statistical analysis, transplanting the healthy mitochondria decreased the cytotoxicity, ROS production, MMP collapse, LPO content, GSSG levels, and caspase-3 activity caused by gentamicin in RPTCs. Also, it has caused an increase in the level of ATP and GSH in the RPTCs. Furthermore, higher preventive effects were observed for the female group. According to the current study, mitochondrial transplantation is a potent therapeutic method in xenobiotic-caused nephrotoxicity., (© 2023. The Society for In Vitro Biology.)

Background: Data on the interplay between sexual hormones balance, platelet function and clinical outcomes of adults with ischemic heart disease (IHD) are still lacking., Objective: To assess the association between the Testosterone (T)-to-Estradiol (E2) Ratio (T/E2) and platelet activation biomarkers in IHD and its predictive value on adverse outcomes., Methods: The EVA study is a prospective observational study of consecutive hospitalized adults with IHD undergoing coronary angiography and/or percutaneous coronary interventions. Serum T/E2 ratios E2, levels of thromboxane B 2 (TxB 2 ) and nitrates (NO), were measured at admission and major adverse events, including all-cause mortality, were collected during a long-term follow-up., Results: Among 509 adults with IHD (mean age 67 ± 11 years, 30% females), males were older with a more adverse cluster of cardiovascular risk factors than females. Acute coronary syndrome and non-obstructive coronary artery disease were more prevalent in females versus males. The lower sex-specific T/E2 ratios identified adults with the highest level of serum TxB 2 and the lowest NO levels. During a median follow-up of 23.7 months, the lower sex-specific T/E2 was associated with higher all-cause mortality (HR 3.49; 95% CI 1.24-9.80; p = 0.018). In in vitro, platelets incubated with T/E2 ratios comparable to those measured in vivo in the lowest quartile showed increased platelet activation as indicated by higher levels of aggregation and TxB 2 production., Conclusion: Among adults with IHD, higher T/E2 ratio was associated with a lower long-term risk of fatal events. The effect of sex hormones on the platelet thromboxane release may partially explain such finding., (© 2022. The Author(s).)

Growth-associated protein 43 (GAP43) is found in skeletal muscle, localized near the calcium release units. In interaction with calmodulin (CaM), it indirectly modulates the activity of dihydropyridine and ryanodine Ca 2+ channels. GAP43-CaM interaction plays a key role in intracellular Ca 2+ homeostasis and, consequently, in skeletal muscle activity. The control of intracellular Ca 2+ signaling is also an important functional requisite in cardiac physiology. The aim of this study is to define the impact of GAP43 on cardiac tissue at macroscopic and cellular levels, using GAP43 knockout (GAP43 -/- ) newborn C57/BL6 mice. Hearts from newborn GAP43 -/- mice were heavier than hearts from wild-type (WT) ones. In these GAP43 -/- hearts, histological section analyses revealed a thicker ventricular wall and interventricular septum with a reduced ventricular chamber area. In addition, increased collagen deposits between fibers and increased expression levels of myosin were observed in hearts from GAP43 -/- mice. Cardiac tropism and rhythm are controlled by multiple intrinsic and extrinsic factors, including cellular events such those linked to intracellular Ca 2+ dynamics, in which GAP43 plays a role. Our data revealed that, in the absence of GAP43, there were cardiac morphological alterations and signs of hypertrophy, suggesting that GAP43 could play a role in the functional processes of the whole cardiac muscle. This paves the way for further studies investigating GAP43 involvement in signaling dynamics at the cellular level., (© 2022. The Author(s).)

The endoplasmic reticulum (ER) is an organelle that orchestrates the production and proper assembly of an extensive types of secretory and membrane proteins. Endoplasmic reticulum stress is conventionally related to prolonged disruption in the protein folding machinery resulting in the accumulation of unfolded proteins in the ER. This disruption is often manifested due to oxidative stress, Ca 2+ leakage, iron imbalance, disease conditions which in turn hampers the cellular homeostasis and induces cellular apoptosis. A mild ER stress is often reverted back to normal. However, cells retaliate to acute ER stress by activating the unfolded protein response (UPR) which comprises three signaling pathways, Activating transcription factor 6 (ATF6), inositol requiring enzyme 1 alpha (IRE1α), and protein kinase RNA-activated-like ER kinase (PERK). The UPR response participates in both protective and pro-apoptotic responses and not much is known about the mechanistic aspects of the switch from pro-survival to pro-apoptosis. When ER stress outpaces UPR response then cell apoptosis prevails which often leads to the development of various diseases including cardiomyopathies. Therefore, it is important to identify molecules that modulate the UPR that may serve as promising tools towards effective treatment of cardiovascular diseases. In this review, we elucidated the latest advances in construing the contribution imparted by the three arms of UPR to combat the adverse environment in the ER to restore cellular homeostasis during cardiomyopathies. We also summarized the various therapeutic agents that plays crucial role in tilting the UPR response towards pro-survival., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cirrhotic cardiomyopathy is a condition where liver cirrhosis is associated with cardiac dysfunction. Triggers and blockers of cirrhotic cardiomyopathy are poorly understood, which might compromise the prognosis of chronic liver disease patients. We tested whether exercise training would reduce liver damage induced by thioacetamide and prevent liver cirrhosis-associated cardiomyopathy. Wistar rats were divided into three groups: control, thioacetamide (TAA), or TAA plus exercise. Thioacetamide increased liver weight and serum alanine aminotransferase and aspartate aminotransferase levels. Also, TAA treatment was involved with hepatic nodule formation, fibrotic septa, inflammatory infiltration, and hepatocyte necrosis. The exercise group presented with a reduction in liver injury status. We found that liver injury was associated with disordered cardiac hypertrophy as well as diastolic and systolic dysfunction. Exercise training attenuated cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment. These results provided insights that exercise training can mitigate cirrhotic cardiomyopathy phenotype. Graphical Abstract Exercise training attenuated liver injury as well as cirrhosis-associated cardiac remodeling and diastolic dysfunction and prevented systolic impairment., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Myocardial infarction leads to cardiomyocyte loss, ensuing ventricular pathological remodeling, dramatic impairment of cardiac function, and ultimately heart failure. Unfortunately, the existing therapeutical treatments cannot directly replenish the lost myocytes in the injured myocardium and the long-term prognosis of heart failure after myocardial infarction remains poor. Growing investigations have demonstrated that the adult mammalian cardiomyocytes possess very limited proliferation capacity, and that was not enough to restore the injured heart. Recently, many studies were targeting to promote cardiomyocyte proliferation via inducing cardiomyocyte cell cycle re-entry for cardiac repair after myocardial infarction. Indeed, these results showed it is a feasible way to stimulate terminally differentiated cardiomyocyte proliferation. Here, we reviewed the major mechanisms and the potential targets for stimulating mammalian adult cardiomyocyte proliferation specifically. This will provide a new therapeutic strategy for the clinical treatment of myocardial infarction by activating the endogenous regeneration. Graphical abstract.

As a tool to support clinical decision-making, Mortality Prediction Models (MPM) can help clinicians stratify and predict patient risk. There are numerous scoring systems for patients with sepsis that predict sepsis-related mortality and the severity of sepsis. But there are currently no MPMs for adults with sepsis who meet the criteria of "good." Clinicians are unlikely to use complex MPMs that require extensive or expensive data collection to impede workflow. Machine learning applied to minimal medical records of patients diagnosed with sepsis can be a useful tool. Progress is needed in the development and validation of clinical decision support tools that can assist in patient risk stratification, prognosis, discussion of patient outcomes, and shared decision making.

Leak of Ca 2+ out of the cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) during diastole is vital to regulate SR Ca 2+ levels. This leak can become deleterious when large spontaneous RyR-mediated Ca 2+ release events evoke proarrhythmic Ca 2+ waves that can lead to delayed after-depolarizations. Here, we model diastolic SR Ca 2+ leak at individual SR Ca 2+ release sites using computer simulations of RyR arrays like those in the dyadic cleft. The results show that RyR arrays size has a significant effect on SR Ca 2+ leak, with bigger arrays producing larger and more frequent Ca 2+ release events. Moreover, big RyR arrays are more susceptible to small changes in the levels of dyadic Ca 2+ buffers. Such changes in buffering shift Ca 2+ leak from small Ca 2+ release events (involving few open RyRs) to larger events (with many open RyRs). Moreover, by analyzing a large parameter space of possible buffering and SR Ca 2+ loads, we find further evidence for the hypothesis that SR Ca 2+ leak by RyR arrays can undergo a sudden phase transition.

The treatment of obstructive sleep apnea-hypopnea syndrome targets the narrow anatomic structure of the upper airway (UA) and lacks an effective therapy for UA dilator muscle dysfunction. Long-term hypoxia can cause damage to UA dilator muscles and trigger a vicious cycle. We previously confirmed that hypoxia-inducible factor 1α (HIF-1α) upregulation mediates muscle fatigue in hypoxia condition, but the underlying mechanism remains to be determined. The present study investigated the intrinsic mechanisms and related pathways of HIF-1α that affect myoblast differentiation, with an aim to search for compounds that have protective effects in hypoxic condition. Differentiation of myoblasts was induced under hypoxia, and we found that hypoxia significantly inhibits the differentiation of myoblasts, damages the ultrastructure of mitochondria, and reduces the expression of myogenin, PGC-1β and pAMPKα1. HIF-1α has a negative regulation effect on AMPK. Downregulation of HIF-1α increases the expression of the abovementioned proteins, promotes the differentiation of myoblasts, and protects mitochondrial integrity. In addition, mitochondrial biogenesis occurs during myogenic differentiation. Inhibition of the AMPK pathway inhibits mitochondrial biogenesis, decreases the level of PGC-1β, and increases apoptosis. Resveratrol dimer can reverse the mitochondrial damage induced by AMPK pathway inhibition and decrease myoblast apoptosis. Our results provided a regulatory mechanism for hypoxic injury in genioglossus which may contribute to the pathogenesis and treatment of OSAHS.

Purpose: Obstructive sleep apnea hypopnea syndrome has been reported to be associated with pulmonary hypertension (PH). Adiponectin (Ad) has many protective roles in the human body, including its function as an anti-inflammatory and an anti-oxidant, as well as its role in preventing insulin resistance and atherosclerosis. This study aimed to investigate the molecular mechanism of chronic intermittent hypoxia (CIH)-induced pulmonary injury and the protective role of Ad in experimental rats., Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups with 10 rats in each group: normal control (NC) group, CIH group, and CIH + Ad group. Rats in the NC group were kept breathing room air for 12 weeks. Rats in the CIH group were intermittently exposed to a hypoxic environment for 8 h/day for 12 weeks. Rats in the CIH + Ad group received 10 μg Ad twice weekly via intravenous injection. After 12 weeks of CIH exposure, we detected the pulmonary function, pulmonary artery pressure, lung histology, pulmonary cell apoptosis, pulmonary artery endothelial cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) level. We also analyzed expression proteins involved in the mitochondria-, endoplasmic reticulum (ER) stress-, and Fas receptor-associated pulmonary apoptosis pathways, as well as the SIRT3/SOD2 pathway., Results: CIH exposure for 12 weeks did not lead to abnormal pulmonary function, PH, or pulmonary artery endothelial cell apoptosis. However, we observed a significant increase in the rate of pulmonary cell apoptosis, the expression of proteins involved in mitochondria-, ER stress-, and Fas receptor-associated pulmonary apoptosis pathways, and the generation of ROS in the CIH group compared with the NC group. In contrast, the MMP and protein expressions of SIRT3/SOD2 pathway were significantly decreased in the CIH group compared with the NC group. Ad supplementation in the CIH + Ad group partially improved these changes induced by CIH., Conclusion: Even though CIH did not cause abnormal pulmonary function or PH, early lung injury was detected at the molecular level in rats exposed to CIH. Treatment with Ad ameliorated the pulmonary injury by activating the SIRT3/SOD2 pathway, reducing ROS generation, and inhibiting ROS-associated lung cell apoptosis.

Atrial fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Even though hypertension, congestive heart failure, pulmonary disease, and coronary artery disease are the potential risk factors for AF, the underlying molecular pathology is largely unknown. The reversion of the mature cardiomyocytes to fetal phenotype, impaired ketone body metabolism, mitochondrial dysfunction, and the cellular effect of reactive oxygen species (ROS) are the major underlying biochemical events associated with the molecular pathology of AF. On this background, the present manuscript sheds light into these biochemical events in regard to the metabolic derangements in cardiomyocyte leading to AF, especially with respect to structural, contractile, and electrophysiological properties. In addition, the article critically reviews the current understanding, potential demerits, and translational strategies in the management of AF.

Glucose transporters are essential for the heart to sustain its function. Due to its nature as a high energy-consuming organ, the heart needs to catabolize a huge quantity of metabolic substrates. For optimized energy production, the healthy heart constantly switches between various metabolites in accordance with substrate availability and hormonal status. This metabolic flexibility is essential for the maintenance of cardiac function. Glucose is part of the main substrates catabolized by the heart and its use is fine-tuned via complex molecular mechanisms that include the regulation of the glucose transporters GLUTs, mainly GLUT4 and GLUT1. Besides GLUTs, glucose can also be transported by cotransporters of the sodium-glucose cotransporter (SGLT) (SLC5 gene) family, in which SGLT1 and SMIT1 were shown to be expressed in the heart. This SGLT-mediated uptake does not seem to be directly linked to energy production but is rather associated with intracellular signalling triggering important processes such as the production of reactive oxygen species. Glucose transport is markedly affected in cardiac diseases such as cardiac hypertrophy, diabetic cardiomyopathy and heart failure. These alterations are not only fingerprints of these diseases but are involved in their onset and progression. The present review will depict the importance of glucose transport in healthy and diseased heart, as well as proposed therapies targeting glucose transporters.