Search

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]

Key points OPA1 is a mitochondrial protein well known to play a fundamental role in the fusion of the inner membrane, in the organization of mitochondrial cristae and in apoptosis., Although the function of mitochondrial dynamics is becoming well understood, its impact on mitochondrial biogenesis is poorly studied, especially in differentiated adult tissues., Here we report a novel finding that in fast skeletal muscles OPA1 deletion impairs training-induced mitochondrial biogenesis., However, our data reveal that Opa1+/− skeletal muscles after training possess better exercise endurance capacity, obviously due to a modification of mitochondrial fatty acid utilization., Thus OPA1 deficiency induces a unique pattern of adaptation to endurance training in fast skeletal muscles., Abstract The role of OPA1, a GTPase dynamin protein mainly involved in the fusion of inner mitochondrial membranes, has been studied in many cell types, but only a few studies have been conducted on adult differentiated tissues such as cardiac or skeletal muscle cells. Yet OPA1 is highly expressed in these cells, and could play different roles, especially in response to an environmental stress like exercise. Endurance exercise increases energy demand in skeletal muscle and repeated activity induces mitochondrial biogenesis and activation of fusion-fission cycles for the synthesis of new mitochondria. But currently no study has clearly shown a link between mitochondrial dynamics and biogenesis. Using a mouse model of haploinsufficiency for the Opa1 gene ( Opa1+/−), we therefore studied the impact of OPA1 deficiency on the adaptation ability of fast skeletal muscles to endurance exercise training. Our results show that, surprisingly, Opa1+/− mice were able to perform the same physical activity as control mice. However, the adaptation strategies of both strains after training differed: while in control mice mitochondrial biogenesis was increased as expected, in Opa1+/− mice this process was blunted. Instead, training in Opa1+/− mice led to an increase in endurance capacity, and a specific adaptive response involving a metabolic remodelling towards enhanced fatty acid utilization. In conclusion, OPA1 appears necessary for the normal adaptive response and mitochondrial biogenesis of skeletal muscle to training. This work opens new perspectives on the role of mitochondrial dynamics in skeletal muscle cells and during adaptation to stress. [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]

Chronic heart failure (CHF), the new epidemic in cardiology, is characterized by energetic failure of both cardiac and skeletal muscles. The failing heart wastes energy due to anatomical changes that include cavity enlargement, altered geometry, tachycardia, mitral insufficiency and abnormal loading, while skeletal muscle undergoes atrophy. Cardiac and skeletal muscles also have altered high-energy phosphate production and handling in CHF. Nevertheless, there are differences in the phenotype of myocardial and skeletal muscle myopathy in CHF: cardiomyocytes have a lower mitochondrial oxidative capacity, abnormal substrate utilisation and intracellular signalling but a maintained oxidative profile; in skeletal muscle, by contrast, mitochondrial failure is less clear, and there is altered microvascular reactivity, fibre type shifts and abnormalities in the enzymatic systems involved in energy distribution. Underlying these phenotypic abnormalities are changes in gene regulation in both cardiac and skeletal muscle cells. Here, we review the latest advances in cardiac and skeletal muscle energetic research and argue that energetic failure could be taken as a unifying mechanism leading to contractile failure, ultimately resulting in skeletal muscle energetic failure, exertional fatigue and death. [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.

Although thyroid hormones induce a well known decrease in muscle oxidative capacity, nothing is known concerning their effects on mitochondrial function and regulation in situ. Similarly, the influence of regeneration process is not completely understood. We investigated the effects of hypothyroidism on mitochondrial function in fast gastrocnemius (GS) and slow soleus (SOL) muscles either intact or having undergone a cycle of degeneration/regeneration (Rg SOL) following a local injection of myotoxin. Thyroid hormone deficiency was induced by thyroidectomy and propylthiouracyl via drinking water. Respiration was measured in muscle fibres permeabilised by saponin in order to assess the oxidative capacity of the muscles and the regulation of mitochondria in situ. Oxidative capacities were 8.9 in SOL, 8.5 in Rg SOL and 5.9 μmol O2/min/g dry weight in GS and decreased by 52, 42 and 39% respectively ( P < 0.001) in hypothyroid rats. Moreover, the Km of mitochondrial respiration for the phosphate acceptor ADP exhibited a two-fold decrease in Rg SOL and intact SOL by hypothyroidism ( P < 0.01), while mitochondrial creatine kinase activity and sensitivity of mitochondrial respiration to creatine were not altered. The results of this study demonstrate that hypothyroidism markedly altered the sensitivity of mitochondrial respiration to ADP but not to creatine in SOL muscles, suggesting that mitochondrial regulation could be partially controlled by thyroid hormones. On the other hand, mitochondrial function completely recovered following regeneration/degeneration, suggesting that thyroid hormones are not involved in the regeneration process per se. [ABSTRACT FROM AUTHOR]

We investigated training-induced changes in biochemical properties and myosin heavy chain (MHC) composition of regenerated (cardiotoxin-injected) plantaris muscles (PLA) in rats either maintained sedentary (S, n = 9) or endurance trained on a treadmill over a 8-week period (T, n = 7). Both endurance training and regeneration altered the pattern of fast MHC expression. An analysis of the two-way interaction between training and regeneration showed that the relative content of type IIa MHC was affected ( P < 0.05). The 140% increase in type IIa MHC observed in regenerated PLA from T rats compared with nontreated muscle of S rats, exceeded the 102% increase resulting from the combination of regeneration alone (26%) and training alone (61%). A similar interaction between training and regeneration was shown for the percentage of fibres expressing either type IIa or type IIb MHC ( P < 0.05). In contrast, a significant increase in the citrate synthase (CS) activity was shown in PLA as a result of endurance training, without specific effect of regeneration. Furthermore, training-induced changes in CK and LDH isoenzyme distribution occurred to a similar extent in regenerated and non-treated PLA muscles, and thus did not follow the changes in MHC isoforms. An increase in the mitochondrial CK isozyme activity (mi-CK) was shown in both non-treated and previously degenerated PLA muscles (123 and 117%, P < 0.01, respectively), without specific effect of regeneration. The ratio of mi-CK to CS activity, an estimate of the mitochondrial specific activity of mi-CK was significantly increased by training ( P < 0.02) and decreased by regeneration ( P < 0.05). Taken together, these data suggest that while training and regeneration have cumulative effects on the pattern of fast MHC expression, the training-induced changes in the energy metabolism shown in mature non-treated myofibres are similar to those observed in regenerated fibres. [ABSTRACT FROM AUTHOR]

Creatine kinase (CK) isoenzymes are present in all vertebrates. An important property of the creatine kinase system is that its total activity, its isoform distribution, and the concentration of guanidino substrates are highly variable among species and tissues. In the highly organized structure of adult muscles, it has been shown that specific CK isoenzymes are bound to intracellular compartments, and are functionally coupled to enzymes and transport systems involved in energy production and utilization. It is however, not established whether functional coupling and intracellular compartmentation are present in all vertebrates. Furthermore, these characteristics seem to be different among different muscle types within a given species. This study will review some of these aspects. It has been observed that: (1) In heart ventricle, CK compartmentation and coupling characterize adult mammalian cells. It is almost absent in frogs, and is weakly present in birds. (2) Efficient coupling of MM-CK to myosin ATPase is seen in adult mammalian striated muscles but not in frog and bird heart where B-CK is expressed instead of M-CK. Thus, the functional efficacy of bound MM-CK to regulate adenine nucleotide turnover within the myofibrillar compartment seems to be specific for muscles expressing M-CK as an integral part of the sarcomere. (3) Mi-CK expression and/or functional coupling are highly tissue and species specific; moreover, they are subject to short term and long term adaptations, and are present late in development. The mitochondrial form of CK (mi-CK) can function in two modes depending on the tissue: (i) in an ≪ADP regeneration mode≫ and (ii) in an ≪ADP amplification mode≫. The mode of action of mi-CK seems to be related to its precise localization within the mitochondrial intermembrane space, whereas its amount might control the quantitative aspects of the coupling. Mi-CK is highly plastic, making it a strong candidate for fine regulation of excitation-contraction coupling in muscles and for energy transfer in cells with large and fluctuating energy demands in general. (4) Although CK isoforms show a binding specificity, the presence of a given isoform within a tissue or a species only, does not predict its functional role. For example, M-CK is expressed before it is functionally compartmentalized within myofibrils during development. Similarly, the presence of ubiquitous or sarcomeric mi-CK isoforms, is not an index of functional coupling of mi-CK to oxidative phosphorylation. (5) Amongst species or muscles, it appears that a large buffering action of the CK system is associated with rapid contraction and high glycolytic activity. On the other hand, an oxidative metabolism is associated with isoform diversity, increased compartmentation, a subsequent low buffering action and efficient phosphotransfer between mitochondria and energy utilization sites. It can be concluded that, in addition to a high variation of total activity and isoform expression, the role of the CK system also critically depends on its intracellular organization and interaction with energy producing and utilizing pathways. This compartmentation will determine the high cellular efficiency and fine specialization of highly organized and differentiated muscle cells. [ABSTRACT FROM AUTHOR]

Very recent experimental data, obtained by using the permeabilized cell technique or tissue homogenates for investigation of the mechanisms of regulation of respiration in the cells in vivo, are shortly summarized. In these studies, surprisingly high values of apparent Km for ADP, exceeding that for isolated mitochondria in vitro by more than order of magnitude, were recorded for heart, slow twitch skeletal muscle, hepatocytes, brain tissue homogenates but not for fast twitch skeletal muscle. Mitochondrial swelling in the hypo-osmotic medium resulted in the sharp decrease of the value of Km for ADP in correlation with the degree of rupture of mitochondrial outer membrane, as determined by the cytochrome c test. Very similar effect was observed when trypsin was used for treatment of skinned fibers, permeabilized cells or homogenates. It is concluded that, in many but not all types of cells, the permeability of the mitochondrial outer membrane for ADP is controlled by some cytoplasmic protein factor(s). Since colchicine and taxol were not found to change high values of the apparent Km for ADP, the participation of microtubular system seems to be excluded in this kind of control of respiration but studies of the roles of other cytoskeletal structures seem to be of high interest. In acute ischemia we observed rapid increase of the permeability of the mitochondrial outer membrane for ADP due to mitochondrial swelling and concomitant loss of creatine control of respiration as a result of dissociation of creatine kinase from the inner mitochondrial membrane. The extent of these damages was decreased by use of proper procedures of myocardial protection showing that outer mitochondrial membrane permeability and creatine control of respiration are valuable indices of myocardial preservation. In contrast to acute ischemia, chronic hypoxia seems to improve the cardiac cell energetics as seen from better postischemic recovery of phosphocreatine, and phosphocreatine overshoot after inotropic stimulation. In general, adaptational possibilities and pathophysiological changes in the mitochondrial outer membrane system point to the central role such a system may play in regulation of cellular energetics in vivo. [ABSTRACT FROM AUTHOR]

The effects of inorganic phosphate (P) on mechanical properties of Triton X100 treated ventricular fibres have been studied in different substrate conditions. In the presence of both MgATP and phosphacreatine, increasing concentrations of P progressively decreased maximal active force, up to 50-60% at 20 mM P. The reduction in stiffness was slightly less. These effects appeared nearly independent of the diameter of the preparations. 20 mM P decreased Ca sensitivity of the myofilaments and increased the Hill coefficient of the tension/pCa relationship; furthermore, the time constant of tension recovery was decreased from 12.9 to 8.9 ms suggesting that the cycling rate of cross-bridges was increased in the presence of P. When MgATP was regenerated by the myofilament bound creatine kinase in the presence of phosphocreatine, P was less efficient in decreasing the maximal tension and it weakened the relaxing effect of MgATP upon rigor tension. These effects are related to the inhibition of creatine kinase by P. The effects of P on maximal force and kinetics of contraction were antagonized by the effects of a decrease in phosphocreatine. The results are discussed in terms of the antagonistic role of P increase and phosphocreatine decrease upon contractile properties of myofilaments during hypoxia in heart muscle. [ABSTRACT FROM AUTHOR]

The author comments on a study published in a recent issue of the journal which examined whether resveratrol can improve physiological adaptations to physical training. Information on the beneficial effects of resveratrol is provided. According to the author, pharmacokinetic data showed that there is poor bioavailability of resveratrol. She points out the safety of resveratrol doses in humans. She questions the mechanism by which resveratrol mimics the effects of exercise.

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.