FK866 compromises mitochondrial metabolism and adaptive stress responses in cultured cardiomyocytes.

AIM: FK866 is an inhibitor of the NAD(+) synthesis rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Using FK866 to target NAD(+) synthesis has been proposed as a treatment for inflammatory diseases and cancer. However, use of FK866 may pose cardiovascular risks, as NAMPT expression is decreased in various cardiomyopathies, with low NAD(+) levels playing an important role in cardiovascular disease progression. In addition, low NAD(+) levels are associated with cardiovascular risk conditions such as aging, dyslipidemia, and type II diabetes mellitus. The aim of this work was to study the effects of FK866-induced NAD(+) depletion on mitochondrial metabolism and adaptive stress responses in cardiomyocytes. METHODS AND RESULTS: FK866 was used to deplete NAD(+) levels in cultured rat cardiomyocytes. Cell viability, mitochondrial metabolism, and adaptive responses to insulin, norepinephrine, and H2O2 were assessed in cardiomyocytes. The drop in NAD(+) induced by FK866 decreased mitochondrial metabolism without changing cell viability. Insulin-stimulated Akt phosphorylation, glucose uptake, and H2O2-survival were compromised by FK866. Glycolytic gene transcription was increased, whereas cardiomyocyte hypertrophy induced by norepinephrine was prevented. Restoring NAD(+) levels via nicotinamide mononucleotide administration reestablished mitochondrial metabolism and adaptive stress responses. CONCLUSION: This work shows that FK866 compromises mitochondrial metabolism and the adaptive response of cardiomyocytes to norepinephrine, H2O2, and insulin.

"Effectiveness of continuous vertebral resonant oscillation using the POLD method in the treatment of lumbar disc hernia". A randomized controlled pilot study.

This study analyses the efficacy of manual oscillatory therapy, following the POLD technique, for acute Lumbar Disc Hernia (LDH) and compares it to usual treatment. A randomised, controlled, triple-blind pilot clinical trial. The sample of 30 patients was divided into two homogeneous groups to receive usual treatment (A) or treatment with the POLD technique (B). We analysed range of motion and subjective variables such as the severity (visual analogue pain scale (VAS)) and extension of the pain. With the application of POLD therapy, patients presented significant changes on range of motion (forward flexion with p < 0.05) at completion of the trial in comparison with the control group. They showed a significant reduction in the severity of pain with a mean VAS scale for lumbar, glutaeus and thigh pain, which improved from 5.09 to 0.79, 5.07 to 0.97 and 4.43 to 0.49 respectively (p < 0.05), and also when compared to usual treatment (p < 0.05) for all body regions. Moreover, we observed a reduction in pain extension (centralization phenomena) (p < 0.001) in comparison with usual treatment. In our study the POLD Method was shown to be an effective manual therapy approach for reducing the severity and irradiation of the pain in LDH patients with sciatica, and more efficient than usual treatment.

Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance.

Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin-proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels. This process is required for mitophagy induced by dexamethasone. Inhibition of mitochondrial fragmentation by Mdivi-1 results in disrupted dexamethasone-induced autophagy/mitophagy. Furthermore, Mdivi-1 increases the expression of genes associated with the atrophy program, suggesting that mitophagy may serve as part of the quality control process in dexamethasone-treated L6 myotubes. Collectively, these data suggest a novel role for dexamethasone-induced autophagy/mitophagy in the regulation of the muscle atrophy program.

Regulation of cardiac autophagy by insulin-like growth factor 1.

Insulin-like growth factor-1 (IGF-1) signaling is a key pathway in the control of cell growth and survival. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3 )/Ca(2+) . The Akt/mTOR and Ras/Raf/ERK signaling arms govern survival in the settings of cardiac stress and hypertrophic growth. By contrast, PLC/InsP3 /Ca(2+) functions to regulate metabolic adaptability and gene transcription. Autophagy is a catabolic process involved in protein degradation, organelle turnover, and nonselective breakdown of cytoplasmic components during nutrient starvation or stress. In the heart, autophagy is observed in a variety of human pathologies, where it can be either adaptive or maladaptive, depending on the context. We proposed the hypothesis that IGF-1 protects the heart by rescuing the mitochondrial metabolism and the energetics state, reducing cell death and controls the potentially exacerbate autophagic response to nutritional stress. In light of the importance of IGF-1 and autophagy in the heart, we review here IGF-1 signaling and autophagy regulation in the context of cardiomyocyte nutritional stress.