Effect of exercise training on cardiac metabolism in rats with heart failure.

Objectives. Heart failure (HF) impairs resting myocardial energetics, myocardial mitochondrial performance, and maximal oxygen uptake (VO2max). Exercise training is included in most rehabilitation programs and benefits HF patients. However, the effect of exercise intensity on cardiac mitochondrial respiration and concentrations of the key bioenergetic metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi) is unclear. This study aimed to investigate the effects of exercise training at different intensities in rats with HF. Methods. Rats underwent myocardial infarction or sham operations and were divided into three subgroups: sedentary, moderate intensity, or high intensity. The impact of HF and 6 weeks of exercise training on energy metabolism was evaluated by 31P magnetic resonance spectroscopy and mitochondrial respirometry. The concentrations of PCr, ATP, and Pi were quantified by magnetic resonance spectroscopy. VO2max was measured by treadmill respirometry. Results. Exercise training increased VO2max in sham and HF. PCr/ATP ratio was reduced in HF (p < .01) and remained unchanged by exercise training. PCr concentration was significantly lower in HF compared to sham (p < .01). Moderate and high-intensity exercise training increased ATP in HF and sham. HF impaired complex I (CI) and complex II (p = .034) respiration. High-intensity exercise training recovered CI respiration in HF rats compared to HF sedentary (p = .014). Conclusions. Exercise training improved cardiac performance, as indicated by increased VO2max and higher exercise capacity, without changing the myocardial PCr/ATP ratio. These observations suggest that the PCr/ATP biomarker is not suited to evaluate the beneficial effects of exercise training in the heart. The exact mechanisms require further investigations, as exercise training did increase ATP levels and CI respiration.

The Effect of Exercise Training on Myocardial and Skeletal Muscle Metabolism by MR Spectroscopy in Rats with Heart Failure.

The metabolism and performance of myocardial and skeletal muscle are impaired in heart failure (HF) patients. Exercise training improves the performance and benefits the quality of life in HF patients. The purpose of the present study was to determine the metabolic profiles in myocardial and skeletal muscle in HF and exercise training using MRS, and thus to identify targets for clinical MRS in vivo. After surgically establishing HF in rats, we randomized the rats to exercise training programs of different intensities. After the final training session, rats were sacrificed and tissues from the myocardial and skeletal muscle were extracted. Magnetic resonance spectra were acquired from these extracts, and principal component and metabolic enrichment analysis were used to assess the differences in metabolic profiles. The results indicated that HF affected myocardial metabolism by changing multiple metabolites, whereas it had a limited effect on skeletal muscle metabolism. Moreover, exercise training mainly altered the metabolite distribution in skeletal muscle, indicating regulation of metabolic pathways of taurine and hypotaurine metabolism and carnitine synthesis.

Skeletal muscle metabolism in rats with low and high intrinsic aerobic capacity: Effect of aging and exercise training.

PURPOSE: Exercise training increases aerobic capacity and is beneficial for health, whereas low aerobic exercise capacity is a strong independent predictor of cardiovascular disease and premature death. The purpose of the present study was to determine the metabolic profiles in a rat model of inborn low versus high capacity runners (LCR/HCR) and to determine the effect of inborn aerobic capacity, aging, and exercise training on skeletal muscle metabolic profile. METHODS: LCR/HCR rats were randomized to high intensity low volume interval treadmill training twice a week or sedentary control for 3 or 11 months before they were sacrificed, at 9 and 18 months of age, respectively. Magnetic resonance spectra were acquired from soleus muscle extracts, and partial least square discriminative analysis was used to determine the differences in metabolic profile. RESULTS: Sedentary HCR rats had 54% and 30% higher VO2max compared to sedentary LCR rats at 9 months and 18 months, respectively. In HCR, exercise increased running speed significantly, and VO2max was higher at age of 9 months, compared to sedentary counterparts. In LCR, changes were small and did not reach the level of significance. The metabolic profile was significantly different in the LCR sedentary group compared to the HCR sedentary group at the age of 9 and 18 months, with higher glutamine and glutamate levels (9 months) and lower lactate level (18 months) in HCR. Irrespective of fitness level, aging was associated with increased soleus muscle concentrations of glycerophosphocholine and glucose. Interval training did not influence metabolic profiles in LCR or HCR rats at any age. CONCLUSION: Differences in inborn aerobic capacity gave the most marked contrasts in metabolic profile, there were also some changes with ageing. Low volume high intensity interval training twice a week had no detectable effect on metabolic profile.

Isogarcinol is a new immunosuppressant.

Calcineurin (CN), a unique protein phosphatase, plays an important role in immune regulation. In this study we used CN as a target enzyme to investigate the immunosuppressive properties of a series of natural compounds from Garcinia mangostana L., and discovered an active compound, isogarcinol. Enzymatic assays showed that isogarcinol inhibited CN in a dose-dependent manner. At concentrations resulting in relatively low cytotoxicity isogarcinol significantly inhibited proliferation of murine spleen T-lymphocytes induced by concanavalin A (ConA) and the mixed lymphocyte reaction (MLR). In addition, it performed much better in acute toxicity tests and via oral administration in mice than cyclosporin A (CsA), with few adverse reactions and low toxicity in experimental animals. Oral administration of isogarcinol in mice resulted in a dose-dependent decrease in delayed type hypersensitivity (DTH) and prolonged graft survival in allogeneic skin transplantation. These findings suggest that isogarcinol could serve as a new oral immunomodulatory drug for preventing transplant rejection, and for long-term medication in autoimmune diseases.