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.

Echinochrome A Treatment Alleviates Atopic Dermatitis-like Skin Lesions in NC/Nga Mice via IL-4 and IL-13 Suppression.

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which skin barrier dysfunction leads to dryness, pruritus, and erythematous lesions. AD is triggered by immune imbalance and oxidative stress. Echinochrome A (Ech A), a natural pigment isolated from sea urchins, exerts antioxidant and beneficial effects in various inflammatory disease models. In the present study, we tested whether Ech A treatment alleviated AD-like skin lesions. We examined the anti-inflammatory effect of Ech A on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like lesions in an NC/Nga mouse model. AD-like skin symptoms were induced by treatment with 1% DNCB for 1 week and 0.4% DNCB for 5 weeks in NC/Nga mice. The results showed that Ech A alleviated AD clinical symptoms, such as edema, erythema, and dryness. Treatment with Ech A induced the recovery of epidermis skin lesions as observed histologically. Tewameter® and Corneometer® measurements indicated that Ech A treatment reduced transepidermal water loss and improved stratum corneum hydration, respectively. Ech A treatment also inhibited inflammatory-response-induced mast cell infiltration in AD-like skin lesions and suppressed the expression of proinflammatory cytokines, such as interferon-γ, interleukin-4, and interleukin-13. Collectively, these results suggest that Ech A may be beneficial for treating AD owing to its anti-inflammatory effects.

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.

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms.

Diabetes mellitus is associated with cardiovascular, ophthalmic, and renal comorbidities. Among these, diabetic cardiomyopathy (DCM) causes the most severe symptoms and is considered to be a major health problem worldwide. Exercise is widely known as an effective strategy for the prevention and treatment of many chronic diseases. Importantly, the onset of complications arising due to diabetes can be delayed or even prevented by exercise. Regular exercise is reported to have positive effects on diabetes mellitus and the development of DCM. The protective effects of exercise include prevention of cardiac apoptosis, fibrosis, oxidative stress, and microvascular diseases, as well as improvement in cardiac mitochondrial function and calcium regulation. This review summarizes the recent scientific findings to describe the potential mechanisms by which exercise may prevent DCM and heart failure.

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.

Aerobic Exercise Training Decreases Hepatic Asprosin in Diabetic Rats.

Asprosin, a novel hormone released from white adipose tissue, regulates hepatic glucose metabolism and is pathologically elevated in the presence of insulin resistance. It is unknown whether aerobic exercise training affects asprosin levels in type 1 diabetes mellitus (T1DM). The aim of this study was to determine whether (1) aerobic exercise training could decrease asprosin levels in the liver of streptozotocin (STZ)-induced diabetic rats and (2) the reduction in asprosin levels could induce asprosin-dependent downstream pathways. Five-week-old male Sprague-Dawley rats were randomly divided into control, STZ-induced diabetes (STZ), and STZ with aerobic exercise training groups (n = 6/group). T1DM was induced by a single dose of STZ (65 mg/kg intraperitoneally (i.p.)). The exercise group was made to run on a treadmill for 60 min at a speed of 20 m/min, 4 days per week for 8 weeks. Aerobic exercise training reduced the protein levels of asprosin, PKA, and TGF-ß but increased those of AMPK, Akt, PGC-1ß, and MnSOD. These results suggest that aerobic exercise training affects hepatic asprosin-dependent PKA/TGF-ß and AMPK downstream pathways in T1DM.

How do medical students actually think while solving problems in three different types of clinical assessments in Korea: Clinical performance examination (CPX), multimedia case-based assessment (CBA), and modified essay question (MEQ).

PURPOSE: This study aimed to explore students' cognitive patterns while solving clinical problems in three different types of assessments - clinical performance examination (CPX), multimedia case-based assessment (CBA), and modified essay question (MEQ) - and thus, to understand how different types of assessments can afford different thinking. METHODS: A total of six test-performance cases from two fourth-year medical students were used for a cross-case study. Data were collected through one-on-one interviews using a stimulated recall protocol where students were: 1) shown videos of themselves taking each assessment and 2) asked to elaborate on what they were thinking. The unit of analysis was the smallest phrases or sentences, from the participants' narratives, representing a meaningful cognitive occurrence. The narrative data were reorganized chronologically and then analyzed according to a frame of hypothetico-deductive reasoning as clinical reasoning. RESULTS: Both participants demonstrated similar patterns in their proportional frequencies of clinical reasoning on the same clinical assessment. The results also revealed that the three different assessment types may afford different aspects of clinical reasoning. For example, the CPX highly promoted the participants' reasoning related to inquiry strategy, while the MEQ highly promoted hypothesis generation. Similarly, the participants' data analysis and synthesis were more afforded by the CBA than the other types. CONCLUSION: This study discovered that different assessment design affords different thinking in problem-solving. This finding can contribute to leveraging ways of improving current clinical assessments. Importantly, the research method used in this study can be utilized as an alternative way of examining the validity of clinical assessments.

The direct effect of lobeglitazone, a new thiazolidinedione, on pancreatic beta cells: A comparison with other thiazolidinediones.

AIMS: The direct effects of thiazolidinediones (TZDs) on pancreatic beta cells have been controversial. The aim of this study was to find out whether a novel TZD, lobeglitazone, has beneficial effects on pancreatic beta cells and db/db mice compared to those of other TZDs. METHODS: INS-1 cells were incubated at a high-glucose concentration with various concentrations of troglitazone, rosiglitazone, pioglitazone, and lobeglitazone. Apoptosis and proliferation of beta cells, markers for ER stress and glucose-stimulated insulin secretion (GSIS) were assessed. In addition, C57BL/6 db/db mice were treated with pioglitazone or lobeglitazone for 4 weeks, and metabolic parameters and the configuration of pancreatic islets were also examined. RESULTS: Lobeglitazone and other TZDs decreased INS-1 cell apoptosis in high-glucose conditions. Lobeglitazone and other TZDs significantly decreased hyperglycemia-induced increases in ER stress markers and increased GSIS. Metabolic parameters showed greater improvement in db/db mice treated with pioglitazone and lobeglitazone than in control mice. Islet size, cell proliferation, and beta cell mass were increased, and collagen surrounding the islets was decreased in treated mice. CONCLUSIONS: Lobeglitazone showed beneficial effects on beta cell survival and function against hyperglycemia. The prosurvival and profunction effects of lobeglitazone were comparable to those of other TZDs.

High Glucose with Insulin Induces Cell Cycle Progression and Activation of Oncogenic Signaling of Bladder Epithelial Cells Cotreated with Metformin and Pioglitazone.

Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.

Cyclic stretch increases mitochondrial biogenesis in a cardiac cell line.

Unlike stable and immobile cell line conditions, animal hearts contract and relax to pump blood throughout the body. Mitochondria play an essential role by producing biological energy molecules to maintain heart function. In this study, we assessed the effect of heart mimetic cyclic stretch on mitochondria in a cardiac cell line. To mimic the geometric and biomechanical conditions surrounding cells in vivo, cyclic stretching was performed on HL-1 murine cardiomyocytes seeded onto an elastic micropatterned substrate (10% elongation, 0.5 Hz, 4 h/day). Cell viability, semi-quantitative Q-PCR, and western blot analyses were performed in non-stimulated control and cyclic stretch stimulated HL-1 cell lines. Cyclic stretch significantly increased the expression of mitochondria biogenesis-related genes (TUFM, TFAM, ERRα, and PGC1-α) and mitochondria oxidative phosphorylation-related genes (PHB1 and CYTB). Western blot analysis confirmed that cyclic stretch increased protein levels of mitochondria biogenesis-related proteins (TFAM, and ERRα) and oxidative phosphorylation-related proteins (NDUFS1, UQCRC, and PHB1). Consequently, cyclic stretch increased mitochondrial mass and ATP production in treated cells. Our results suggest that cyclic stretch transcriptionally enhanced mitochondria biogenesis and oxidative phosphorylation without detrimental effects in a cultured cardiac cell line.

Hemodynamics in diabetic human aorta using computational fluid dynamics.

Three-dimensional (3D) computational aortic models have been established to reproduce aortic diseases such as aortic aneurysm and dissection; however, no such models have been developed to study diabetes mellitus (DM). To characterize biomechanical properties of the human aorta with DM, reconstructed aortic CT images were converted into DICOM format, and imported into the 3D segmentation using Mimics software. This resulted in a 3D reconstruction of the complete aorta, including three branches. We applied a pulsatile blood pressure waveform for the ascending aorta to provide a biomimetic environment using COMSOL Multiphysics software. Hemodynamics were compared between the control and DM models. We observed that mean blood flow velocity, aortic pressure, and von Mises stress values were lower in the DM model than in the control model. Furthermore, the range of aortic movement was lower in the DM model than in the control model, suggesting that the DM aortic wall is more susceptible to rupture. When comparing biomechanical properties in discrete regions of the aorta, all values were higher in the ascending aorta for both control and DM models, corresponding to the location of most aortic lesions. We have developed a compute based that integrates advanced image processing strategies and computational techniques based on finite element method to perform hemodynamics analysis based on CT images. Our study of image-based CFD analysis hopes to provide a better understanding of the relationship between aortic hemodynamic and developing pathophysiology of aortic diseases.

Pharmacologic inhibition of AKT leads to cell death in relapsed multiple myeloma.

Multiple myeloma (MM) is a neoplastic plasma cell disorder with high disease recurrence rates. Novel therapeutic approaches capable of improving outcomes in patients with MM are urgently required. The AKT signalling plays a critical regulatory role in MM pathophysiology, including survival, proliferation, metabolism, and has emerged as a key therapeutic target. Here, we identified a novel AKT inhibitor, HS1793, and defined its mechanism of action and clinical significance in MM. HS1793 disrupted the interaction between AKT and heat shock protein 90, resulting in protein phosphatase 2A-modulated phosphorylated-AKT (p-AKT) reduction. Moreover, we observed reductions in the kinase activity of the AKT downstream target, IκB kinase alpha, and the transcriptional activity of nuclear factor kappa B, which induced mitochondria-mediated cell death in MM cells exclusively. We confirmed the cytotoxicity and specificity of HS1793 via PET-CT imaging of a metastatic mouse model generated using human MM cells. We also evaluated the cytotoxic effects of HS1793 in primary and relapsed MM cells isolated from patients. Thus, HS1793 offers great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients.

A Novel Atypical PKC-Iota Inhibitor, Echinochrome A, Enhances Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells.

Echinochrome A (EchA) is a marine bioproduct extracted from sea urchins having antioxidant, antimicrobial, anti-inflammatory, and chelating effects, and is the active component of the clinical drug histochrome. We investigated the potential use of Ech A for inducing cardiomyocyte differentiation from mouse embryonic stem cells (mESCs). We also assessed the effects of Ech A on mitochondrial mass, inner membrane potential (Δψm), reactive oxygen species generation, and levels of Ca2+. To identify the direct target of Ech A, we performed in vitro kinase activity and surface plasmon resonance binding assays. Ech A dose-dependently enhanced cardiomyocyte differentiation with higher beating rates. Ech A (50 µM) increased the mitochondrial mass and membrane potential but did not alter the mitochondrial superoxide and Ca2+ levels. The in vitro kinase activity of the atypical protein kinase C-iota (PKCι) was significantly decreased by 50 µM of Ech A with an IC50 for PKCι activity of 107 µM. Computational protein-ligand docking simulation results suggested the direct binding of Ech A to PKCι, and surface plasmon resonance confirmed the direct binding with a low KD of 6.3 nM. Therefore, Ech A is a potential drug for enhancing cardiomyocyte differentiation from mESCs through direct binding to PKCι and inhibition of its activity.

Ursolic acid in health and disease.

Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti-oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements.

Aerobic exercise training decreases cereblon and increases AMPK signaling in the skeletal muscle of STZ-induced diabetic rats.

Cereblon (CRBN) has been reported as a negative regulator of adenosine monophosphate-activated protein kinase (AMPK). Aerobic exercise training has been shown to increase AMPK, which resulted in glucose regulation in skeletal muscle. However, the expression level of CRBN and its association with the physiological modulation of glucose are still unclear. Male Sprague-Dawley rats (5-week-old, n = 18) were assigned to control, streptozotocin (STZ, 65 mg/kg)-induced diabetic group, and STZ + exercise (STZ + EXE) group with six rats in each group. Rats in the STZ + EXE group exercised by treadmill running (20 m/min, 60 min, 4 times/week) for 8 weeks. Compared with the STZ group, blood glucose was significantly decreased in the STZ + EXE group. The skeletal muscle of rats in the STZ + EXE group showed a significant decrease in CRBN levels and an increase in AMPK, protein kinase B, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, fibronectin type III domain-containing protein 5, glucose transporter type 4, superoxide dismutase 1, and uncoupling protein 3 levels. These results suggest that CRBN is a potential regulator of glucose homeostasis in the skeletal muscle. Moreover, our results suggest that aerobic exercise training may provide an important physiological treatment for type 1 diabetes by decreasing CRBN and increasing AMPK signaling in skeletal muscle.

Exercise training causes a partial improvement through increasing testosterone and eNOS for erectile function in middle-aged rats.

PURPOSE: Aging changes the balance of sex hormones and causes endothelial dysfunction in the penis, both of which are important determinants of erectile dysfunction (ED). The purpose of this study was to evaluate whether exercise training could protect against erectile dysfunction by increasing serum testosterone and penile eNOS levels in aging rats. METHODS: A total of 14 young (2-month-old) and 14 middle-aged (18-month-old) Sprague Dawley rats were randomly assigned to either untrained control (young control, [YC], middle-aged control, [MC]) or endurance exercise-trained (young exercise, [YE], middle-aged exercise, [ME]) groups with seven rats per group. The exercise groups trained with treadmill running for 6 weeks. Body composition parameters (body weight, heart mass, liver mass, and testicular mass), serum sex hormone levels (testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin), endothelial function-related parameters in the penis (endothelial nitric oxide synthase [eNOS], CD31, alpha smooth muscle actin [α-SMA]), and maximal intracavernous pressure measure (ICP) and total ICP were analyzed in middle-aged rats. RESULTS: The middle-aged groups showed increased body weight, as compared with the young groups, but exercise training attenuated the aging-induced increase in body weight. The middle-aged groups had lower testicular mass compared with the young groups, but exercise training attenuated aging-induced decreases in testicular mass. Exercise training increased serum testosterone levels in both the young and middle-aged groups. However, there were no changes in the levels of luteinizing hormone, follicle-stimulating hormone, and prolactin among the groups. MC group showed decreased protein levels of p-eNOS, as compared with the YC group. However, exercise training protected against aging-induced decrease in eNOS and p-eNOS protein levels in the penis. Interestingly, exercise training also increased protein levels of α-SMA and maximal ICP in the middle-aged group. CONCLUSIONS: Exercise training has beneficial effects on erectile function in aged rats through increased testosterone production from the testis and strengthening of the cavernous endothelium with activation of eNOS. Therefore, exercise training may be a therapeutic modality for improving erectile dysfunction associated with aging.

Alternative splicing isoforms in health and disease.

Alternative splicing (AS) of protein-coding messenger RNAs is an essential regulatory mechanism in eukaryotic gene expression that controls the proper function of proteins. It is also implicated in the physiological regulation of mitochondria and various ion channels. Considering that mis-splicing can result in various human diseases by modifying or abrogating important physiological protein functions, a fine-tuned balance of AS is essential for human health. Accumulated data highlight the importance of alternatively spliced isoforms in various diseases, including neurodegenerative disorders, cancer, immune and infectious diseases, cardiovascular diseases, and metabolic conditions. However, basic understanding of disease mechanisms and development of clinical applications still require the integration and interpretation of physiological roles of AS. This review discusses the roles of AS in health and various diseases, while highlighting potential AS-targeting therapeutic applications.

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.