Experimental evidence and clinical implications of Warburg effect in the skeletal muscle of Fabry disease.

Skeletal muscle (SM) pain and fatigue are common in Fabry disease (FD). Here, we undertook the investigation of the energetic mechanisms related to FD-SM phenotype. A reduced tolerance to aerobic activity and lactate accumulation occurred in FD-mice and patients. Accordingly, in murine FD-SM we detected an increase in fast/glycolytic fibers, mirrored by glycolysis upregulation. In FD-patients, we confirmed a high glycolytic rate and the underutilization of lipids as fuel. In the quest for a tentative mechanism, we found HIF-1 upregulated in FD-mice and patients. This finding goes with miR-17 upregulation that is responsible for metabolic remodeling and HIF-1 accumulation. Accordingly, miR-17 antagomir inhibited HIF-1 accumulation, reverting the metabolic-remodeling in FD-cells. Our findings unveil a Warburg effect in FD, an anaerobic-glycolytic switch under normoxia induced by miR-17-mediated HIF-1 upregulation. Exercise-intolerance, blood-lactate increase, and the underlying miR-17/HIF-1 pathway may become useful therapeutic targets and diagnostic/monitoring tools in FD.

Physical Exercise: A Novel Tool to Protect Mitochondrial Health.

Mitochondrial dysfunction is a crucial contributor to heart diseases. Alterations in energetic metabolism affect crucial homeostatic processes, such asATP production, the generation of reactive oxygen species, and the release of pro-apoptotic factors, associated with metabolic abnormalities. In response to energetic deficiency, the cardiomyocytes activate the Mitochondrial Quality Control (MQC), a critical process in maintaining mitochondrial health. This process is compromised in cardiovascular diseases depending on the pathology's severity and represents, therefore, a potential therapeutic target. Several potential targeting molecules within this process have been identified in the last years, and therapeutic strategies have been proposed to ameliorate mitochondria monitoring and function. In this context, physical exercise is considered a non-pharmacological strategy to protect mitochondrial health. Physical exercise regulates MQC allowing the repair/elimination of damaged mitochondria and synthesizing new ones, thus recovering the metabolic state. In this review, we will deal with the effect of physical exercise on cardiac mitochondrial function tracing its ability to modulate specific steps in MQC both in physiologic and pathologic conditions.

Effects of Chronic Supplementation of L-Arginine on Physical Fitness in Water Polo Players.

BACKGROUND: Ergogenic nutritional supplementation is sought by professional athletes for improving physical performance; nevertheless, scientific evidence to support the chronic use of L-Arginine among water polo players is missing. METHODS: Seventeen male professional water polo players were randomly assigned to assume 5 grams per day of L-Arginine (n = 9) or placebo (n = 8) for 4 weeks. The players' fitness level was assessed in the maximal speed swimming test. Ear lobe blood samples taken before and after the effort for serum lactate content were analyzed. A speed-to-lactate ratio was generated at the baseline and after 4 weeks of treatment. We also tested the effects of L-Arginine in vitro, measuring NO production, mitochondrial respiration, and gene expression in human fibroblasts. RESULTS: L-Arginine did not modify BMI, muscle strength, and maximal speed at 200 meters after 4 weeks. However, L-Arginine ameliorated oxidative metabolism to exercise as suggested by the statistically significant lower lactate-to-speed ratio, which was not observed in placebo-treated controls. In vitro, L-Arginine induced the expression of a key regulator of mitochondrial biogenesis (PGC1α) and genes encoding for complex I and increased the production of nitric oxide and the maximal oxygen consumption rate. CONCLUSIONS: Chronic L-Arginine is safe and effective in ameliorating the oxidative metabolism of professional water polo players, through a mechanism of enhanced mitochondrial function.

Diagnostic performance of myocardial perfusion imaging with conventional and CZT single-photon emission computed tomography in detecting coronary artery disease: A meta-analysis.

BACKGROUND: We performed a meta-analysis to compare the diagnostic performance of conventional SPECT (C-SPECT) and cadmium-zinc-telluride (CZT)-SPECT systems in detecting angiographically proven coronary artery disease (CAD). METHODS: Studies published between January 2000 and February 2018 were identified by database search. We included studies assessing C-SPECT or CZT-SPECT as a diagnostic test to evaluate patients for the presence of CAD, defined as at least 50% diameter stenosis on invasive coronary angiography. A study was eligible regardless of whether patients were referred for suspected or known CAD. RESULTS: We identified 40 eligible articles (25 C-SPECT and 15 CZT-SPECT studies) including 7334 patients (4997 in C-SPECT and 2337 in CZT-SPECT studies). The pooled sensitivity and specificity were 85% and 66% for C-SPECT and 89% and 69% for CZT-SPECT imaging studies. The area under the curve was slightly higher for CZT-SPECT (0.89) compared to C-SPECT (0.83); accordingly, the summary diagnostic OR was 17 for CZT-SPECT and 11 for C-SPECT. The accuracy of the two tests slightly differs between C-SPECT and CZT-SPECT (chi-square 11.28, P < .05). At meta-regression analysis, no significant association between both sensitivity and specificity and demographical and clinical variables considered was found for C-SPECT and CZT-SPECT studies. CONCLUSIONS: C-SPECT and CZT-SPECT have good diagnostic performance in detecting angiographic proven CAD, with a slightly higher accuracy for CZT-SPECT. This result supports the use of the novel gamma cameras in clinical routine practices also considering the improvements in acquisition time and radiation exposure reduction.

Head-to-head comparison of diagnostic accuracy of stress-only myocardial perfusion imaging with conventional and cadmium-zinc telluride single-photon emission computed tomography in women with suspected coronary artery disease.

BACKGROUND: Breast attenuation may impact the diagnostic accuracy of stress myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT). We compared the performance of conventional (C)-SPECT and cadmium-zinc-telluride (CZT)-SPECT systems in women with low-intermediate likelihood of coronary artery disease (CAD). METHODS AND RESULTS: A total of 109 consecutive women underwent stress-optional rest MPI by both C-SPECT and CZT-SPECT. In the overall study population, a weak albeit significant correlation between total perfusion defect (TPD) measured by C-SPECT and CZT-SPECT was observed (r = 0.38, P < .001) and at Bland-Altman analysis the mean difference in TPD (C-SPECT minus CZT-SPECT) was 2.40% (P < .001). Overall concordance of semi-quantitative diagnostic performance between C-SPECT and CZT-SPECT was observed in 52 (48%) women with a κ value of 0.09. Normalcy rate was significantly higher using CZT-SPECT compared to C-SPECT (P < .001). Machine learning analysis performed through the implementation of J48 algorithm proved that CZT-SPECT has higher sensitivity, specificity, and accuracy than C-SPECT. CONCLUSIONS: In women with low-intermediate likelihood of CAD, there is a poor concordance of diagnostic performance between C-SPECT and CZT-SPECT, and CZT-SPECT allows better normalcy rate detection compared to C-SPECT.

Antidiabetic and Cardioprotective Effects of Pharmacological Inhibition of GRK2 in db/db Mice.

Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help the management of diabetes and its cardiovascular complications at the same time. GRK2 appears a promising target, given its established role in insulin resistance and in systolic heart failure. Using a custom peptide inhibitor of GRK2, we assessed in vitro in L6 myoblasts the effects of GRK2 inhibition on glucose extraction and insulin signaling. Afterwards, we treated diabetic male mice (db/db) for 2 weeks. Glucose tolerance (IGTT) and insulin sensitivity (ITT) were ameliorated, as was skeletal muscle glucose uptake and insulin signaling. In the heart, at the same time, the GRK2 inhibitor ameliorated inflammatory and cytokine responses, reduced oxidative stress, and corrected patterns of fetal gene expression, typical of diabetic cardiomyopathy. GRK2 inhibition represents a promising therapeutic target for diabetes and its cardiovascular complications.