The Activation of the LIMK/Cofilin Signaling Pathway via Extracellular Matrix-Integrin Interactions Is Critical for the Generation of Mature and Vascularized Cardiac Organoids.

The generation of mature and vascularized human pluripotent stem cell-derived cardiac organoids (hPSC-COs) is necessary to ensure the validity of drug screening and disease modeling. This study investigates the effects of cellular aggregate (CA) stemness and self-organization on the generation of mature and vascularized hPSC-COs and elucidates the mechanisms underlying cardiac organoid (CO) maturation and vascularization. COs derived from 2-day-old CAs with high stemness (H-COs) and COs derived from 5-day-old CAs with low stemness (L-COs) were generated in a self-organized microenvironment via Wnt signaling induction. This study finds that H-COs exhibit ventricular, structural, metabolic, and functional cardiomyocyte maturation and vessel networks consisting of endothelial cells, smooth muscle cells, pericytes, and basement membranes compared to L-COs. Transcriptional profiling shows the upregulation of genes associated with cardiac maturation and vessel formation in H-COs compared with the genes in L-COs. Through experiments with LIMK inhibitors, the activation of ROCK-LIMK-pCofilin via ECM-integrin interactions leads to cardiomyocyte maturation and vessel formation in H-COs. Furthermore, the LIMK/Cofilin signaling pathway induces TGFß/NODAL and PDGF pathway activation for the maturation and vascularization of H-COs. The study demonstrates for the first time that LIMK/Cofilin axis activation plays an important role in the generation of mature and vascularized COs.

The emerging roles of Shank3 in cardiac function and dysfunction.

Shank3 is a member of the Shank family proteins (Shank1-3), which are abundantly present in the postsynaptic density (PSD) of neuronal excitatory synapses. As a core scaffold in the PSD, Shank3 plays a critical role in organizing the macromolecular complex, ensuring proper synaptic development and function. Clinically, various mutations of the SHANK3 gene are causally associated with brain disorders such as autism spectrum disorders and schizophrenia. However, recent in vitro and in vivo functional studies and expression profiling in various tissues and cell types suggest that Shank3 also plays a role in cardiac function and dysfunction. For example, Shank3 interacts with phospholipase Cß1b (PLCß1b) in cardiomyocytes, regulating its localization to the sarcolemma and its role in mediating Gq-induced signaling. In addition, changes in cardiac morphology and function associated with myocardial infarction and aging have been investigated in a few Shank3 mutant mouse models. This review highlights these results and potential underlying mechanisms, and predicts additional molecular functions of Shank3 based on its protein interactors in the PSD, which are also highly expressed and function in the heart. Finally, we provide perspectives and possible directions for future studies to better understand the roles of Shank3 in the heart.

Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes.

An aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of INa,Late in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca2+ imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca2+ release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased INa,Late and were significantly mediated by treatment with the INa,Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased INa,Late and subsequent aberrant myocyte excitability, which were abolished by INa,Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic INa,Late. These results indicate that PI3K/Akt signaling is critical for regulating INa,Late and electrical remodeling, supporting the use of PI3K/Akt-mediated INa,Late as a therapeutic target for AF.

Stretchable and Directly Patternable Double-Layer Structure Electrodes with Complete Coverage.

Stretchable electrodes are widely used in next-generation wearable electronics. Recent studies incorporated designs that help rigid electrodes attain stretchability. However, these structures exhibited unsatisfactory charge/signal extraction efficiency because of their low areal fill factor. Additionally, they cannot be photolithographically patterned on polymer substrates because of their low adhesion, requiring additional complicated fabrication steps. We developed photolithographically patternable stretchable electrodes with complete coverage and enhanced charge-extraction efficiency. The electrodes, comprising double layers, included a chemically treated Ag nanowire mesh and Au thin film. The interfacial linker role of polyvinylpyrrolidone chemically strengthened the interfacial bonds, and the reinforced concrete structure of nanowire-embedded metal thin films enhanced the mechanical properties. Therefore, the electrodes provided superior efficiency and stability in capturing physical, electromagnetic, and electrophysiological signals while exceeding the existing stretchable electrode limits. A broad range of applications are foreseen, such as electrocardiogram sensing electrodes, strain sensors, temperature sensors, and antennas.

Cereblon contributes to cardiac dysfunction by degrading Cav1.2α.

AIMS: Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. METHODS AND RESULTS: Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. CONCLUSION: Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.

Novel GSK-3ß Inhibitor Neopetroside A Protects Against Murine Myocardial Ischemia/Reperfusion Injury.

Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2-related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.

Modeling Hypoxic Stress In Vitro Using Human Embryonic Stem Cells Derived Cardiomyocytes Matured by FGF4 and Ascorbic Acid Treatment.

Mature cardiomyocytes (CMs) obtained from human pluripotent stem cells (hPSCs) have been required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. Here, we found that FGF4 and ascorbic acid (AA) induce differentiation of BG01 human embryonic stem cell-cardiogenic mesoderm cells (hESC-CMCs) into mature and ventricular CMs. Co-treatment of BG01 hESC-CMCs with FGF4+AA synergistically induced differentiation into mature and ventricular CMs. FGF4+AA-treated BG01 hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes and potential cardiac biomarkers proved in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated BG01 hESC-CMs in response to hypoxia based on transcriptome analyses. This study demonstrates that it is feasible to model hypoxic stress in vitro using hESC-CMs matured by soluble factors.

LEFTY-PITX2 signaling pathway is critical for generation of mature and ventricular cardiac organoids in human pluripotent stem cell-derived cardiac mesoderm cells.

The generation of mature ventricular cardiomyocytes (CMs) resembling adult CMs from human pluripotent stem cells (hPSCs) is necessary for disease modeling and drug discovery. To investigate the effect of self-organizing capacity on the generation of mature cardiac organoids (COs), we generated cardiac mesoderm cell-derived COs (CMC-COs) and CM-derived COs (CM-COs) and evaluated COs. CMC-COs exhibited more organized sarcomere structures and mitochondria, well-arranged t-tubule structures, and evenly distributed intercalated discs. Increased expressions of ventricular CM, cardiac metabolic, t-tubule formation, K+ ion channel, and junctional markers were confirmed in CMC-COs. Mature ventricular-like function such as faster motion vector speed, decreased beats per min, increased peak-to-peak duration, and prolonged APD50 and APD90 were observed in CMC-COs. Transcriptional profiling revealed that extracellular matrix-integrin, focal adhesion, and LEFTY-PITX2 signaling pathways are upregulated in CMC-COs. LEFTY knockdown affected ECM-integrin-FA signaling pathways in CMC-COs. Here, we found that high self-organizing capacity of CMCs is critical for the generation of mature and ventricular COs. We also demonstrated that LEFTY-PITX2 signaling plays key roles for CM maturation and specification into ventricular-like CM subtype in CMC-COs. CMC-COs are an attractive resource for disease modeling and drug discovery.

BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes.

Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.

Circadian modulation of the cardiac proteome underpins differential adaptation to morning and evening exercise training: an LC-MS/MS analysis.

All living beings on earth are influenced by the circadian rhythm, the rising and the setting of the sun. The ubiquitous effect of exercise is widely believed to maximize health benefits but has not been formally investigated for cardiac responses in the exercise-induced circadian rhythms. We hypothesized that the exercise-related proteome is differentially influenced by circadian rhythm and analyzed the differences between the effects of morning and evening exercise. Twenty-four Sprague-Dawley rats were randomly divided into four groups (n = 6 per group): morning control, morning exercise, evening control, and evening exercise groups. The exercise groups were subjected to 12-week treadmill exercise (5 days/week) performed either during daytime or nighttime. After 12 weeks, the physiological characteristics (e.g., body weight, heart weight, visceral fat, and blood metabolites), cardiovascular capacity (ejection fraction (%) and fractional shortening (%)), circadian gene expression levels (clock, ball1, per1, per2, cry1, and cry2), and the proteomic data were obtained and subjected to univariate and multivariate analysis. The mRNA levels of per1 and cry2 increased in the evening group compared with those in the morning group. We also found that per2 decreased and cry2 increased in the evening exercise groups. The evening exercise groups showed more decreased triacylglycerides and increased blood insulin levels than the morning exercise group. The principal component analysis, partial least squares discriminant analysis, and orthogonal partial least squares discriminant analysis indicated that the circadian rhythm differently influenced the protein networks of the exercise groups. In the morning exercise group, the transcription-translation feedback loop (TTFL) (clock, per1, per2, cry1, and cry2) formed a protein-protein interaction network with Nme2, Hint1, Ddt, Ndufb8, Ldha, and Eef1a2. In contrast, the TTFL group appeared close to Maoa, Hist2h4, and Macrod1 in the evening exercise group. Interestingly, the evening exercise group decreased the mRNA level of per2 but not per1. Per1 and Per2 are known to transport Cry1 and Cry2 into the nucleus. Taken together, we summarized the characteristics of enriched proteins in the aspect of their molecular function, cellular component, and biological process. Our results might provide a better understanding of the circadian effect on exercise-related proteins.

mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells.

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

Tetrahydrobiopterin enhances mitochondrial biogenesis and cardiac contractility via stimulation of PGC1α signaling.

Tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous target in cardiovascular diseases. Although it is involved in cardiovascular metabolism and mitochondrial biology, its mechanisms of action are unclear. We investigated how BH4 regulates cardiovascular metabolism using an unbiased multiple proteomics approach with a sepiapterin reductase knock-out (Spr-/-) mouse as a model of BH4 deficiency. Spr-/- mice exhibited a shortened life span, cardiac contractile dysfunction, and morphological changes. Multiple proteomics and systems-based data-integrative analyses showed that BH4 deficiency altered cardiac mitochondrial oxidative phosphorylation. Along with decreased transcription of major mitochondrial biogenesis regulatory genes, including Ppargc1a, Ppara, Esrra, and Tfam, Spr-/- mice exhibited lower mitochondrial mass and severe oxidative phosphorylation defects. Exogenous BH4 supplementation, but not nitric oxide supplementation or inhibition, rescued these cardiac and mitochondrial defects. BH4 supplementation also recovered mRNA and protein levels of PGC1α and its target proteins involved in mitochondrial biogenesis (mtTFA and ERRα), antioxidation (Prx3 and SOD2), and fatty acid utilization (CD36 and CPTI-M) in Spr-/- hearts. These results indicate that BH4-activated transcription of PGC1α regulates cardiac energy metabolism independently of nitric oxide and suggests that BH4 has therapeutic potential for cardiovascular diseases involving mitochondrial dysfunction.

Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts.

Metabolic disturbance and mitochondrial dysfunction are a hallmark of diabetic cardiomyopathy (DC). Resistance exercise (RE) not only enhances the condition of healthy individuals but could also improve the status of those with disease. However, the beneficial effects of RE in the prevention of DC and mitochondrial dysfunction are uncertain. Therefore, this study investigated whether RE attenuates DC by improving mitochondrial function using an in vivo rat model of diabetes. Fourteen Otsuka Long-Evans Tokushima Fatty rats were assigned to sedentary control (SC, n = 7) and RE (n = 7) groups at 28 weeks of age. Long-Evans Tokushima Otsuka rats were used as the non-diabetic control. The RE rats were trained by 20 repetitions of climbing a ladder 5 days per week. RE rats exhibited higher glucose uptake and lower lipid profiles, indicating changes in energy metabolism. RE rats significantly increased the ejection fraction and fractional shortening compared with the SC rats. Isolated mitochondria in RE rats showed increase in mitochondrial numbers, which were accompanied by higher expression of mitochondrial biogenesis proteins such as proliferator-activated receptor-γ coactivator-1α and TFAM. Moreover, RE rats reduced proton leakage and reactive oxygen species production, with higher membrane potential. These results were accompanied by higher superoxide dismutase 2 and lower uncoupling protein 2 (UCP2) and UCP3 levels in RE rats. These data suggest that RE is effective at ameliorating DC by improving mitochondrial function, which may contribute to the maintenance of diabetic cardiac contractility.

Generation of PDGFRα+ Cardioblasts from Pluripotent Stem Cells.

Isolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα+Flk1- cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197. This novel population of actively proliferating cells is cardiac lineage-committed but in a morphologically and functionally immature state compared to mature cardiomyocytes. Most important, most of CsAYTE-induced PCBs spontaneously differentiated into functional αMHC+ cardiomyocytes (M+CMs) and could be a potential cellular resource for cardiac regeneration.

Formyl Peptide Receptor 2 Is Involved in Cardiac Repair After Myocardial Infarction Through Mobilization of Circulating Angiogenic Cells.

Increasing evidence suggests that circulating angiogenic cells (CACs) promote repair of ischemic tissues. Activation of formyl peptide receptor 2 (Fpr2) has been reported to stimulate repair of ischemic heart. This study was conducted to investigate the role of Fpr2 on CAC mobilization and cardiac protection in myocardial infarction (MI). WKYMVm, a strong agonist for Fpr2, was administered in a murine model of acute MI, and mobilization of CACs including endothelial progenitor cells (CD34+ Flk1+ or Sca1+ Flk1+ cells) in peripheral blood was monitored. CAC mobilization by daily injection of WKYMVm for the first 4 days after MI was as efficient as granulocyte colony-stimulating factor and provided myocardial protection from apoptosis with increased vascular density and preservation of cardiac function. Transplantation of bone marrow (BM) from green fluorescent protein mice showed that BM-derived cells homed to ischemic heart after WKYMVm treatment and contributed to tissue protection. Transplantation of BM from Fpr2 knockout mice showed that Fpr2 in BM cells is critical in mediation of WKYMVm-stimulated myocardial protection and neovascularization after MI. These results suggest that activation of Fpr2 in BM after WKYMVm treatment provides cardiac protection through mobilization of CACs after MI, which may lead to the development of a new clinical protocol for treating patients with ischemic heart conditions. Stem Cells 2017;35:654-665.

Mitochondrial pyruvate dehydrogenase phosphatase 1 regulates the early differentiation of cardiomyocytes from mouse embryonic stem cells.

Mitochondria are crucial for maintaining the properties of embryonic stem cells (ESCs) and for regulating their subsequent differentiation into diverse cell lineages, including cardiomyocytes. However, mitochondrial regulators that manage the rate of differentiation or cell fate have been rarely identified. This study aimed to determine the potential mitochondrial factor that controls the differentiation of ESCs into cardiac myocytes. We induced cardiomyocyte differentiation from mouse ESCs (mESCs) and performed microarray assays to assess messenger RNA (mRNA) expression changes at differentiation day 8 (D8) compared with undifferentiated mESCs (D0). Among the differentially expressed genes, Pdp1 expression was significantly decreased (27-fold) on D8 compared to D0, which was accompanied by suppressed mitochondrial indices, including ATP levels, membrane potential, ROS and mitochondrial Ca(2+). Notably, Pdp1 overexpression significantly enhanced the mitochondrial indices and pyruvate dehydrogenase activity and reduced the expression of cardiac differentiation marker mRNA and the cardiac differentiation rate compared to a mock control. In confirmation of this, a knockdown of the Pdp1 gene promoted the expression of cardiac differentiation marker mRNA and the cardiac differentiation rate. In conclusion, our results suggest that mitochondrial PDP1 is a potential regulator that controls cardiac differentiation at an early differentiation stage in ESCs.

Cereblon in health and disease.

Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Mice with genetic depletion of CRBN are resistant to various stress conditions including a high-fat diet, endoplasmic reticulum stress, ischemia/reperfusion injury, and alcohol-related liver damage. In this review, we discuss the various roles of CRBN in human health and disease and suggest avenues for further research to enhance our basic knowledge and clinical application of CRBN.

Voluntary stand-up physical activity enhances endurance exercise capacity in rats.

Involuntary physical activity induced by the avoidance of electrical shock leads to improved endurance exercise capacity in animals. However, it remains unknown whether voluntary stand-up physical activity (SPA) without forced simulating factors improves endurance exercise capacity in animals. We examined the eff ects of SPA on body weight, cardiac function, and endurance exercise capacity for 12 weeks. Twelve male Sprague-Dawley rats (aged 8 weeks, n=6 per group) were randomly assigned to a control group (CON) or a voluntary SPA group. The rats were induced to perform voluntary SPA (lifting a load equal to their body weight), while the food height (18.0 cm) in cages was increased progressively by 3.5 every 4 weeks until it reached 28.5 cm for 12 weeks. The SPA group showed a lower body weight compared to the CON group, but voluntary SPA did not affect the skeletal muscle and heart weights, food intake, and echocardiography results. Although the SPA group showed higher grip strength, running time, and distance compared to the CON group, the level of irisin, corticosterone, genetic expression of mitochondrial biogenesis, and nuclei numbers were not affected. These findings show that voluntary SPA without any forced stimuli in rats can eff ectively reduce body weight and enhance endurance exercise capacity, suggesting that it may be an important alternative strategy to enhance endurance exercise capacity.

Influence of starvation on heart contractility and corticosterone level in rats.

The physiological changes, including cardiac modification, that occur during starvation are not yet completely understood. The purpose of this study is to examine the effects of a 2-week starvation period on heart contractility, muscle mass, and irisin and corticosterone levels in rats. Rats in the starved group showed a significant reduction in the body, heart, kidney, and muscle weight (n = 23, p < 0.05). Blood glucose, total protein, and albumin showed a 44, 17.5, and 10.3 % reduction, respectively (p < 0.05). Lipid reserves, such as total lipid, triglyceride, and free fatty acid, were also comparably reduced (p < 0.05). However, the bilirubin, creatinine, blood urea nitrogen, and creatine kinase levels were higher than in the control group (p < 0.05). The blood irisin level was unchanged, but the stress-related corticosterone level was significantly higher in the starved group. The differences observed in M-mode echocardiography were further compared with the body-weight-matched control group. Starvation reduced the left ventricle mass; however, this difference was not significant compared with the body-weight-matched group (p > 0.05). In the starvation group, the impairment of cardiac output was dependent on the reduction in stroke volume and heart rate. Starvation induced a severe reduction in ejection fraction and fractional shortening when compared with the body-weight-matched control group (p < 0.05). In summary, prolonged starvation, which leads to a deficiency of available nutrition, increases the stress-related corticosterone level, impairs the cardiac output, and is associated with changes in cardiac morphogeometry.