Mitochondrial energy metabolism in heart failure: a question of balance.
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ABSTRACT:
SUBMITTER: Huss JM
PROVIDER: S-EPMC1052011 | biostudies-literature | 2005 Mar
REPOSITORIES: biostudies-literature
Publications
Mitochondrial energy metabolism in heart failure: a question of balance.
Huss Janice M JM Kelly Daniel P DP
The Journal of clinical investigation 20050301 3
The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure. ...[more]
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Project description:Cardiac failure is the most prevalent cause of death at higher age, and is commonly associated with impaired energy homeostasis in the heart. Mitochondrial metabolism appears critical to sustain cardiac function to counteract aging. In this study, we generated mice transgenically over-expressing the mitochondrial protein frataxin, which promotes mitochondrial energy conversion by controlling iron-sulfur-cluster biogenesis and hereby mitochondrial electron flux. Hearts of transgenic mice displayed increased mitochondrial energy metabolism and induced stress defense mechanisms, while overall oxidative stress was decreased. Following standardized exposure to doxorubicin to induce experimental cardiomyopathy, cardiac function and survival was significantly improved in the transgenic mice. The insulin/IGF-1 signaling cascade is an important pathway that regulates survival following cytotoxic stress through the downstream targets protein kinase B, Akt, and glycogen synthase kinase 3. Activation of this cascade is markedly inhibited in the hearts of wild-type mice following induction of cardiomyopathy. By contrast, transgenic overexpression of frataxin rescues impaired insulin/IGF-1 signaling and provides a mechanism to explain enhanced cardiac stress resistance in transgenic mice. Taken together, these findings suggest that increased mitochondrial metabolism elicits an adaptive response due to mildly increased oxidative stress as a consequence of increased oxidative energy conversion, previously named mitohormesis. This in turn activates protective mechanisms which counteract cardiotoxic stress and promote survival in states of experimental cardiomyopathy. Thus, induction of mitochondrial metabolism may be considered part of a generally protective mechanism to prevent cardiomyopathy and cardiac failure.
| S-EPMC3006026 | biostudies-other
Project description:We conducted RNAseq using mRNA extracted from rat hearts to elucidate the effect of doxorubicin chemotherapy on the heart. Rats were 250g at the start of the treatment protocol. Tissues were collected post five weekly intravenous injections of either sterile saline or 3mg/kg/week doxorubicin. Hearts were excised under deep isoflurane anaesthesia and rapidly frozen with liquid-nitrogen cooled Wallenberger tongs. Total mRNA was extracted with a Qiagen RNeasy fibrous tissue mini kit. Gene set enrichement analysis (GSEA) shows that unlike previously reported, oxidative stress is not involved in the cardiac pathology of our model (reduced cardiac function and atrophy). However, gene sets responsible for mRNA processing, ribosomes and protein synthesis and processing are decreased in doxorubicin-treated rat hearts compared to saline control hearts.
2020-11-10 | GSE154603 | GEO
Project description:Aim: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite synthesized in host organisms from specific food constituents, such as choline, carnitine and betaine. During the last decade, elevated TMAO levels have been proposed as biomarkers to estimate the risk of cardiometabolic diseases. However, there is still no consensus about the role of TMAO in the pathogenesis of cardiovascular disease since regular consumption of TMAO-rich seafood (i.e., a Mediterranean diet) is considered to be beneficial for the primary prevention of cardiovascular events. Therefore, the aim of this study was to investigate the effects of long-term TMAO administration on mitochondrial energy metabolism in an experimental model of right ventricle heart failure. Methods: TMAO was administered to rats at a dose of 120 mg/kg in their drinking water for 10 weeks. Then, a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) was administered to induce right ventricular dysfunction, and treatment with TMAO was continued (experimental groups: Control; TMAO; MCT; TMAO+MCT). After 4 weeks, right ventricle functionality was assessed by echocardiography, mitochondrial function and heart failure-related gene and protein expression was determined. Results: Compared to the control treatment, the administration of TMAO (120 mg/kg) for 14 weeks increased the TMAO concentration in cardiac tissues up to 14 times. MCT treatment led to impaired mitochondrial function and decreased right ventricular functional parameters. Although TMAO treatment itself decreased mitochondrial fatty acid oxidation-dependent respiration, no effect on cardiac functionality was observed. Long-term TMAO administration prevented MCT-impaired mitochondrial energy metabolism by preserving fatty acid oxidation and subsequently decreasing pyruvate metabolism. In the experimental model of right ventricle heart failure, the impact of TMAO on energy metabolism resulted in a tendency to restore right ventricular function, as indicated by echocardiographic parameters and normalized organ-to-body weight indexes. Similarly, the expression of a marker of heart failure severity, brain natriuretic peptide, was substantially increased in the MCT group but tended to be restored to control levels in the TMAO+MCT group. Conclusion: Elevated TMAO levels preserve mitochondrial energy metabolism and cardiac functionality in an experimental model of right ventricular heart failure, suggesting that under specific conditions TMAO promotes metabolic preconditioning-like effects.
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Project description:Profile gene expression change in 3T3 L1 adipocytes after overexpression of microRNA mir-17/18a, mir-18a/19a/20a, and mir-19b/92a
2015-06-19 | E-MTAB-2662 | biostudies-arrayexpress
Project description:Background:In recent years, the application of Shenmai (SM) injection, a traditional Chinese medicine (TCM), to treat heart failure (HF) has been gradually accepted in China. However, whether SM improves energy metabolism in patients with HF has not been determined due to the lack of high-quality studies. We aimed to investigate the influence of SM on energy metabolism in patients with HF. Methods:This single-blind, controlled study randomly assigned 120 eligible patients equally into three groups receiving SM, trimetazidine (TMZ), or control in addition to standard medical treatment for HF for 7 days. The primary endpoints were changes in free fatty acids (FFAs), glucose, lactic acid (LA), pyroracemic acid (pyruvate, PA) and branched chain amino acids (BCAAs) in serum. The secondary outcomes included the New York Heart Association (NYHA) functional classification, TCM syndrome score (TCM-s), left ventricular injection fraction (LVEF), left ventricular internal diastolic diameter (LVIDd), left ventricular internal dimension systole (LVIDs), and B-type natriuretic peptide (BNP). Results:After treatment for 1 week, the NYHA functional classification, TCM-s, and BNP level gradually decreased in the patients in all three groups, but these metrics were significantly increased in the patients in the SM group compared with those in the patients in the TMZ and control groups (P < 0.05). Moreover, energy metabolism was improved in the NYHA III-IV patients in the SM group compared with those in the patients in the TMZ and control groups as evidenced by changes in the serum levels of FFA, LA, PA, and BCAA. Conclusions:Integrative treatment with SM in addition to standard medical treatment for HF was associated with improved cardiac function compared to standard medical treatment alone. The benefit of SM in HF may be related to an improvement in energy metabolism, which seems to be more remarkable than that following treatment with TMZ.
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Project description:Cardiac metabolic remodeling is recognized as an important hallmark of heart failure (HF), while strategies that target energy metabolism have therapeutic potential in treating HF. Shen-Fu formula (S-F) is a standardized herbal preparation frequently used in clinical practice and is a promising combinatorial therapy for HF-related metabolic remodeling. Herein, we performed an untargeted multi-omics analysis using transcriptomics, proteomics, and metabolomics on HF mice induced by transverse aortic constriction (TAC). Integrated and pathway-driven analyses were used to reveal the therapeutic targets associated with S-F treatment. The cardioprotective effect and potential mechanism of S-F were verified by the results from echocardiography, hemodynamics, histopathology, and biochemical assays. As a result, S-F significantly alleviated myocardial fibrosis and hypertrophy, thus reducing the loss of heart function during adverse cardiac remodeling in TAC mice. Integrated omics analysis showed that S-F synergistically mediated the metabolic flexibility of fatty acids and glucose in cardiac energy metabolism. These effects of S-F were confirmed by the activation of AMP-activated protein kinase (AMPK) and its downstream targets in the failing heart. Collectively, our results demonstrated that S-F suppressed cardiac metabolic remodeling through activating AMPK-related pathways via energy-dependent mechanisms.
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Project description:Shp2, a Src homology 2-containing tyrosine phosphatase, has been implicated in a variety of growth factor or cytokine signaling pathways. However, it is conceivable that this enzyme acts predominantly in one pathway versus the others in a cell, depending on the cellular context. To determine the putative functions of Shp2 in the adult brain, we selectively deleted Shp2 in postmitotic forebrain neurons by crossing CaMKIIalpha-Cre transgenic mice with a conditional Shp2 mutant (Shp2(flox)) strain. Surprisingly, a prominent phenotype of the mutant (CaMKIIalpha-Cre:Shp2(flox/flox) or CaSKO) mice was the development of early-onset obesity, with increased serum levels of leptin, insulin, glucose, and triglycerides. The mutant mice were not hyperphagic but developed enlarged and steatotic liver. Consistent with previous in vitro data, we found that Shp2 down-regulates Jak2/Stat3 (signal transducer and activator of transcription 3) activation by leptin in the hypothalamus. However, Jak2/Stat3 down-regulation is offset by a dominant Shp2 promotion of the leptin-stimulated Erk pathway, leading to induction rather than suppression of leptin resistance upon Shp2 deletion in the brain. Collectively, these results suggest that a primary function of Shp2 in postmitotic forebrain neurons is to control energy balance and metabolism, and that this phosphatase is a critical signaling component of leptin receptor ObRb in the hypothalamus. Shp2 shows potential as a neuronal target for pharmaceutical sensitization of obese patients to leptin action.
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Project description:C1q/TNF-related proteins (CTRP1-15) constitute a conserved group of secreted proteins of the C1q family with diverse functions. In vitro studies have shown that CTRP11/C1QL4 can inhibit adipogenesis, antagonize myoblast fusion, and promote testosterone synthesis and secretion. Whether CTRP11 is required for these processes in vivo remains unknown. Here, we show that knockout (KO) mice lacking CTRP11 have normal skeletal muscle mass and function, and testosterone level, suggesting that CTRP11 is dispensable for skeletal muscle development and testosterone production. We focused our analysis on whether this nutrient-responsive secreted protein plays a role in controlling sugar and fat metabolism. At baseline when mice are fed a standard chow, CTRP11 deficiency affects metabolic parameters in a sexually dimorphic manner. Only Ctrp11-KO female mice have significantly higher fasting serum ketones and reduced physical activity. In the refeeding phase following food withdrawal, Ctrp11-KO female mice have reduced food intake and increased metabolic rate and energy expenditure, highlighting CTRP11's role in fasting-refeeding response. When challenged with a high-fat diet to induce obesity and metabolic dysfunction, CTRP11 deficiency modestly exacerbates obesity-induced glucose intolerance, with more pronounced effects seen in Ctrp11-KO male mice. Switching to a low-fat diet after obesity induction results in greater fat loss in wild type relative to KO male mice, suggesting impaired response to obesity reversal and reduced metabolic flexibility in the absence of CTRP11. Collectively, our data provide genetic evidence for novel sex-dependent metabolic regulation by CTRP11, but note the overall modest contribution of CTRP11 to systemic energy homeostasis.
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