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We examined effects of moderate-intensity endurance training on muscle COX/CS activities and V'O2max in control WT and IL-6-/- mice. Animals were exercised for 10 weeks on treadmill for 1 h, 5 days a week at velocity of 6 m · min-1 which was increased by 0.5 m · min-1 every 2 weeks up to 8 m · min-1. Training triggered an increase of enzyme activities in soleus muscle of WT mice (COX: 480.3 ± 8.9 U · g-1 in sedentary group vs. 773.3 ± 62.6 U · g-1 in trained group, P < 0.05 and CS: 374.0 ± 6.0 U · g-1 in sedentary group vs. 534.2 ± 20.5 U · g-1 in trained group, P < 0.01, respectively) whereas no changes were observed in soleus of IL6-/- mice. Moreover, in mixed gastrocnemius muscle of trained IL-6-/- mice enzyme activities tended to be lower (COX: 410.7 ± 48.4 U · g-1 for sedentary vs. 277.0 ± 36.5 U · g-1 for trained group and CS: 343.8 ± 24.6 U · g-1 for sedentary vs. 251.7 ± 27.1 U · g-1 for trained group). No changes in V'O2max were observed in WT and IL-6-/- mice after training. Concluding, moderate-velocity endurance training-induced increase in COX and CS activities in muscles of WT mice only which suggests that IL-6 regulates training-induced skeletal muscle responses to exercise. [ABSTRACT FROM AUTHOR]

Background Resistance to the insulin-sensitising adipocytokine, adiponectin, has been described at the level of the skeletal muscle in patients with chronic heart failure (CHF). Objective To investigate whether exercise training (ET) would improve skeletal muscle energy metabolism and adiponectin signalling. Methods In a prospective cohort study, patients with CHF were recruited from the Cardiac Rehabilitation Centre, Antwerp University Hospital. They underwent 4months' combined endurance-resistance ET. Skeletal muscle mRNA and protein expression of adiponectin, AdipoR1 and downstream metabolic genes were measured. Results Adiponectin mRNA expression in the nine CHF patients was higher than that in 10 matched healthy subjects (p=0.007), whereas AdipoR1 and downstream-located genes involved in lipid (PPAR-[alpha], ACADM) and glucose metabolism (AMPK, hexokinase2) were down-regulated. Skeletal muscle AdipoR1 correlated with VO(2) peak (r=0.900; p=0.001), maximal workload (r=0.753; p=0.019) and steady state workload (r=0.928; p<0.001). ET increased maximal workload and muscle strength. In addition, ET lowered adiponectin mRNA expression (p=0.017), whereas the expression of AdipoR1 (p=0.011) and downstream metabolic genes was increased to levels comparable to those in healthy subjects. ELISA confirmed the normalisation of skeletal muscle adiponectin expression at the protein level (p=0.047). Conclusion At the level of the skeletal muscle, CHF patients are characterised by increased adiponectin expression and decreased expression of AdipoR1 and downstream metabolic genes. ET normalises the mRNA expression of adiponectin and AdipoR1 and reverses disorders in lipid and glucose metabolism in skeletal muscle. These alterations in metabolic gene expression may help to understand the beneficial effects of ET in CHF. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system plays an important role in the hydroelectrolytic balance, blood pressure regulation, and cell growth. In some studies, the insertion (I) allele of the angiotensin-converting enzyme (ACE) gene, associated with a lower ACE activity, has been found in excess frequency in elite endurance athletes, suggesting that decreased ACE activity could be involved in endurance performance (Myerson S, Hemingway H, Budget R, Martin J, Humphries S, and Montgomery H. J Appl Physiol 87: 1313-1316, 1999). To test this hypothesis, we evaluated whether ACE inhibition could be associated with improved endurance performance and muscle oxidative capacity in rats. Eight male Wistar rats were treated for 10-12 wk with an ACE inhibitor, perindopril (2 mg·kg[sup -1]·day[sup -1]), and compared with eight control rats. Endurance time was measured on a treadmill, and oxidative capacity and regulation of mitochondrial respiration by substrates were evaluated in saponin-permeabilized fibers of slow soleus and fast gastrocnemius muscles. Endurance time did not differ between groups (57 ± 5 min for perindopril vs. 55 ± 6 min for control). Absolute and relative (to body weight) left ventricular weight was 20% (P < 0.01) and 12% (P < 0.01) lower, respectively, in the treated group. No difference in oxidative capacity, mitochondrial enzyme activities, or mitochondrial regulation by ADP was observed in soleus or gastrocnemius. Mitochondrial respiration with glycerol 3-phosphate was 17% higher in gastrocnemius (P < 0.03) and with octanoylcarnitine 14% greater in soleus (P < 0.01) of treated rats. These results demonstrate that ACE inhibition was not associated with improved endurance time and maximal oxidative capacity of skeletal muscles. This suggests that ACE activity has no implication in endurance capacity and only minor effects on mitochondrial function in sedentary animals. [ABSTRACT FROM AUTHOR]

Examines the effects of functional overload on phenotypic remodeling in regenerated skeletal muscle. Use of the bilateral surgical ablation; Decrease in the activity of the M subunit of lactate dehydrogenase; Alteration on the control of gene expression in regenerated muscle.

Introduction Disruption of Endoplasmic Reticulum (ER) homeostasis, a condition referred to as ER stress, has been implicated in many cardiovascular diseases. In response to ER stress, several beneficial physiological adaptive response of the cell are triggered, such as autophagy. Mitophagy is a dynamic process responsible for the degradation of mitochondria by the lysosomal pathway. However, severe ER stress triggers autophagic cell death/apoptosis and exacerbates cardiac dysfunction. Objective In this context, we chose to study the role of sirtuin 1 (Sirt1), a deacetylase activated in response to many cardiac stresses to promote cell survival, as modulator of ER stress–induced mitophagy in the heart. Method In our study, H9c2 cells (rat cardiomyoblasts) were treated with the well-known ER stress inducer tunicamycin (TN, 10 μg/mL) and showed time course an increase of ER stress marker (GRP78, CHOP) and autophagy (LC3-II and Cyto-ID ® ) markers. By flow cytometry and western blot, we studied the role of SIRT1 in ER stress-induced mitophagy. In vivo, we analysed the effect of TN injection (2 mg/kg) in inductible Sirt1 knock out mice and we observed mitophagy by electron microscopy. Results We have shown that TN induces ER stress and autophagy in H9c2 cells. Moreover inhibition/extinction of Sirt1 by EX-527/siRNA decreased ER stress-induced mitophagy to a level similar to that of the two well known autophagy inhibitors, 3-methyl adenine and chloroquine. In vivo, TN injection triggered a sustained ER stress response who amplifies cardiac dysfunction in inductible Sirt1 knock out mice and we observed that TN induced mitophagy. Conclusion Our results show that activation of Sirt1 promotes the induction of mitophagy in response to ER stress, protecting the cardiac cells from cell death. Sirt1 thus appears as an interesting therapeutic target to modulate adaptive autophagy in ER stress-associated cardiac pathologies. [ABSTRACT FROM AUTHOR]

Aims Endoplasmic reticulum (ER) stress has recently emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. However, the molecular mechanisms by which ER stress leads to cardiac dysfunction remain poorly understood. Methods and results In the present study, we evaluated the early cardiac effects of ER stress induced by tunicamycin (TN) in mice. Electrocardiographic analysis indicated that TN-induced ER stress led to a significant impairment of the cardiac function. Electron microscopic observations revealed that ultrastructural changes of cardiomyocytes in response to ER stress manifested extensively at the level of the sarco-endoplasmic reticulum membranes. Smooth tubules of sarcoplasmic reticulum in connection with short sections of rough endoplasmic reticulum were observed. The presence of rough instead of smooth reticulum was increased at the interfibrillar space, at the level of dyads and in the vicinity of mitochondria. At a functional level, ER stress resulted in a substantial decrease in mitochondrial biogenesis as demonstrated by the decrease of the expression of PGC-1α and of its targets NRF1, Tfam, CS and COXIV. ER stress also led to an impairment of mitochondrial oxidative phosphorylation and to a metabolic remodeling characterized by a shift from fatty acid to glycolytic substrate consumption. Conclusion Our findings show that ER stress induces cytoarchitectural and metabolic alterations in cardiomyocytes and provide evidences that ER stress could represent a primary mechanism that contributes to the impairment of energy metabolism reported in most cardiac diseases. [ABSTRACT FROM AUTHOR]

An abstract of the article "Voluntary Physical Activity Alterations in Endothelial Nitric Oxide Synthase Knock-Out Mice," by I. Momken and colleagues, is presented.

An abstract of the article "Generalized Metabolic Myopathy in Pressure Overload-Induced Heart Failure: Is Circulating Angiotensin II Involved," by I. Momken and colleagues, is presented.

An abstract of the article "Role of Calcineurin in Chronic Hypoxia-Induced Hypertrophic Response of Right Ventricle" by N. Koulmann and colleagues is presented.

An abstract of the study "PGC-1alpha correlates with cardiac and skeletal muscle oxidative capacity in heart failure," by A. Garnier et al, is presented.

An abstract of the article "The Intrinsic Mitochondrial Oxidative Capacity of Human Failing Hearts Is Depressed and Relates to Disease Severity But Keeps Normal Regulatory Properties," by B. Mettauer and colleagues, is presented.

An abstract of the article "Effects of ACE Inhibition on Mitochondrial Substrates Utilization Pathways of Cardiac and Skeletal Muscles in Rats Postmyocardial Infarction," by J. Zoll and colleagues, is presented.

An abstract of the article "Quantitative and Qualitative Mitochondrial Adaptations of Substrates Utilization in Cardiac and Skeletal Muscles," by E. Ponsot and colleagues, is presented.

Abstract: Cardiac energy metabolism is a determinant of the response to hypertrophic stimuli. To investigate how it responds to physiological or pathological stimuli, we compared the energetic status in models of hypertrophy induced by physiological stimuli (pregnancy or treadmill running) and by pathological stimulus (spontaneously hypertensive rats, SHR) in 15 week-old female rats, leading to a 10% cardiac hypertrophy. Late stage of compensated hypertrophy was also studied in 25 week-old SHR (35% of hypertrophy). Markers of cardiac remodelling did not follow a unique pattern of expression: in trained rats, only ANF was increased; in gravid rats, calcineurin activation and BNP expression were reduced while β-MHC expression was enhanced; all markers were clearly up-regulated in 25 week-old SHR. Respiration of permeabilized fibers revealed a 17% increase in oxidative capacity in trained rats only. Mitochondrial enzyme activities, expression of the master regulator PGC-1α and mitochondrial transcription factor A, and content of mitochondrial DNA were not consistently changed, suggesting that compensated hypertrophy does not involve alterations of mitochondrial biogenesis. Mitochondrial fatty acid utilization tended to increase in trained rats and decreased by 14% in 15 week-old SHR. Expression of markers of lipid oxidation, PPARα and its down-stream targets MCAD and CPTI, was up-regulated after training and tended to decrease in gravid and 15 week-old SHR rats. Taken together these results show that there is no univocal pattern of cardiac adaptation in response to physiological or pathological hypertrophic stimuli, suggesting that other factors could play a role in determining adaptation of energy metabolism to increased workload. [Copyright &y& Elsevier]

Abstract: Creatine kinase (CK) is a phosphotransfer kinase that catalyzes the reversible transfer of a phosphate moiety between ADP and creatine and that is highly expressed in skeletal muscle. In fast glycolytic skeletal muscle, deletion of the cytosolic M isoform of CK in mice (M-CK−/−) leads to a massive increase in the oxidative capacity and of mitochondrial volume. This study was aimed at investigating the transcriptional pathways leading to mitochondrial biogenesis in response to CK deficiency. Wild type and M-CK−/− mice of eleven months of age were used for this study. Gastrocnemius muscles of M-CK−/− mice exhibited a dramatic increase in citrate synthase (+120%) and cytochrome oxidase (COX, +250%) activity, and in mitochondrial DNA (+60%), showing a clear activation of mitochondrial biogenesis. Similarly, mRNA expression of the COXI (mitochondria-encoded) and COXIV (nuclear-encoded) subunits were increased by +103 and +94% respectively. This was accompanied by an increase in the expression of the nuclear respiratory factor (NRF2α) and the mitochondrial transcription factor (mtTFA). Expression of the co-activator PGC-1α, a master gene in mitochondrial biogenesis was not significantly increased while that of PGC-1β and PRC, two members of the same family, was moderately increased (+45% and +55% respectively). While the expression of the modulatory calcineurin-interacting protein 1 (MCIP1) was dramatically decreased (−68%) suggesting inactivation of the calcineurin pathway, the metabolic sensor AMPK was activated (+86%) in M-CK−/− mice. These results evidence that mitochondrial biogenesis in response to a metabolic challenge exhibits a unique pattern of regulation, involving activation of the AMPK pathway. [Copyright &y& Elsevier]