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Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol
No full textHeart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta(1)-beta(2)-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a beta(1) selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective beta-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance
Malondialdehyde as a biomarker for oxidative stress. Application to skeletal muscle atrophy.
No full textSkeletal muscle fibers synthesis in heart failure: role of PGC-1 alpha, calcineurin and GH
No full textBackground: Patients with congestive heart failure (CHF) have decreased exercise capacity because of muscle fatigability. Symptoms are due to a specific myopathy with increased expression of fast type 11 fibres, fast MHCs and muscle atrophy. PGC-1 alpha, a potent transcriptional coactivator for nuclear receptors, induces mitochondrial myogenesis and the preferential synthesis of slow fibres. IGF1-Calcineurin stimulation can lead to increased expression of PGC-1 alpha. Methods: We investigated the levels of PGC-1 alpha during progression and regression of skeletal myopathy in the soleus muscle of rats with right heart failure secondary to monocrotaline-induced pulmonary hypertension. We used GH to stimulate the IGF1-calcineurin-PGC-1 alpha axis. Results: The slow MHC1 decreased from 90.6 +/- 0.5 to 71.7 +/- 2.2 in the CHF rats (p<0.00001) and increased to 82.1 +/- 1.8 after GH (p<0.00002). Western blot analysis showed that PGC-1 alpha is significantly decreased in CHF, while it came back to control values after GH. Cytochrome c was decreased in CHF and returned to control values with GH. Troponin I was expressed solely as slow isoform in the control soleus, while the fast isoform appeared in CHF. Its expression returned to control values after GH. Conclusions: We conclude that PGC-1 alpha plays an important role in regulating slow fibres expression. PGC1-1 alpha is in turn regulated by the IGF1-calcineurin axis. GH by increasing the circulating levels of IGF1, enhanced the expression of slow MHC1, TnI and the synthesis of mitochondria. (c) 2005 Elsevier Ireland Ltd. All rights reserved
Curcumin counteracts both atrophy and loss of force of soleus muscles after hindlimb unloading
No full textSkeletal muscle atrophy induced by microgravity, immobilization or prolonged bed rest, represents
a major invalidating condition. Although redox imbalance fosters disuse atrophy, anti-oxidant
administration provided controversial results. Here we investigated the effects of curcumin, a
vegetal polyphenol with pleomorphic biological activity, on rat soleus muscles exposed to
simulated microgravity (tail-suspension) for 7 days. Curcumin treatment countered by
approximately 30% the loss of soleus mass and myofiber cross-sectional area (CSA) following
unloading (P < 0.02). In vitro contractile properties of unloaded soleus muscle showed a dramatic
decrease of both absolute and specific maximal forces. Curcumin administration potently countered
the force loss in unloaded muscles, whereas it did not affect muscle contractility of control rats. The
recovery of tetanic force with curcumin indicates that the treatment favours the maintenance of
both muscular mass and contractility. Indexes of muscle protein and lipid oxidation, such as protein
carbonylation, revealed by Oxyblot, and malondialdehyde, measured with HPLC, were significantly
blunted by curcumin in unloaded rats compared to sham-treated ones (P = 0.01). Furthermore,
curcumin significantly antagonized in unloaded solei both the decrease of Grp94, a stress
protein/chaperone involved in anti-oxidant cytoprotection, and the increase of HO-1, a recognized
marker of oxidative stress. The mechanistically involvement of Grp94 in the curcumin-induced
attenuation of myofiber atrophy was further suggested by the lower CSA displayed by myofibers
transfected with antisense Grp94 cDNA in unloaded curcumin-treated rats.
In conclusion, curcumin represents an effective and safe tool to upregulate muscle Grp94 level and
maintain muscle function during exposure to microgravity
Stress response as a tool to monitor and to counteract progression of muscular atrophy. Validation of Oxyblot techniques using microbiopsies.
No full textCurcumin counteracts loss of force and atrophy of hindlimb unloaded rat soleus by hampering neuronal nitric oxide synthase untethering from sarcolemma.
No full textAntioxidant administration aimed to antagonize the development and progression of disuse muscle atrophy provided controversial results. Here we investigated the effects of curcumin, a vegetal polyphenol with pleiotropic biological activity, because of its ability to upregulate glucose-regulated protein 94 kDa (Grp94) expression in myogenic cells. Grp94 is a sarco-endoplasmic reticulum chaperone, the levels of which decrease significantly in unloaded muscle. Rats were injected intraperitoneally with curcumin and soleus muscle was analysed after 7 days of hindlimb unloading or standard caging. Curcumin administration increased Grp94
protein levels about twofold in muscles of ambulatory rats (P < 0.05) and
antagonized its decrease in unloaded ones. Treatment countered loss of soleus mass and myofibre cross-sectional area by approximately 30% (P ≤ 0.02) and maintained a force-frequency relationship closer to ambulatory levels. Indexes of muscle protein and lipid oxidation, such as protein carbonylation, revealed by Oxyblot, and malondialdehyde, measured with HPLC, were significantly blunted in unloaded treated rats compared to untreated ones (P = 0.01). Mechanistic involvement of Grp94 was suggested by the disruption of curcumin-induced attenuation of myofibre atrophy after transfection with antisense grp94 cDNA and by the drug-positive effect on the maintenance of the subsarcolemmal localization
of active neuronal nitric oxide synthase molecules, which were displaced to thesarcoplasm by unloading. The absence of additive effects after combined administration of a neuronal nitric oxide synthase inhibitor further supported curcumin interference with this pro-atrophic pathway. In conclusion, curcumin represents an effective and safe tool to upregulate Grp94 muscle levels and to maintain muscle function during unweighting
ATROPHY, PROTEIN OXIDATION AND CELLULAR STRESS RESPONSE OF DISUSED HUMAN SKELETAL MUSCLE. THE OSMA BED-REST STUDY - VALDOLTRA 2007.
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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