Beneficial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure.
ABSTRACT Muscle atrophy is a determinant of exercise capacity in heart failure (CHF). Myocyte apoptosis, triggered by tumor necrosis factor-alpha (TNF-alpha) or its second messenger sphingosine (SPH), is one of the causes of atrophy. Growth hormone (GH) improves hemodynamic and cardiac trophism in several experimental models of CHF, but its effect on skeletal muscle in CHF is not yet clear. We tested the hypothesis that GH can prevent skeletal muscle apoptosis in rats with CHF. CHF was induced by injecting monocrotaline. After 2 wk, 2 groups of rats were treated with GH (0.2 mg.kg(-1).day(-1) and 1.0 mg.kg(-1).day(-1)) subcutaneously. A third group of controls had saline. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, myosin heavy chain (MHC) composition, and a study on myocyte apoptosis and serum levels of TNF-alpha and SPH were carried out. The number of apoptotic nuclei, muscle atrophy, and serum levels of TNF-alpha and SPH were decreased with GH at high but not at low doses compared with CHF rats. Bcl-2 was increased, whereas activated caspases and bax were decreased. The MHC pattern in GH-treated animals was similar to that of controls. Monocrotaline slowed down both contraction and relaxation but did not affect specific tetanic force, whereas absolute force was decreased. GH treatment restored contraction and relaxation to control values and brought muscle mass and absolute twitch and tetanic tension to normal levels. These findings may provide an insight into the therapeutic strategy of GH given to patients with CHF to improve exercise capacity.
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ABSTRACT: This work investigated the effects of 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294) treatment on the contractile response of soleus (SOL) muscle from rats submitted to myocardial infarction (MI). Following coronary artery ligation, LASSBio-294 (2 mg/kg, i.p.) or vehicle was administrated once daily for 4 weeks. The run time to fatigue for sham rats was 17.9±2.6 min, and it was reduced to 3.3±0.8 min (P<0.05) in MI rats. In MI rats treated with LASSBio-294, the time to fatigue was 15.1±3.6 min. During the contractile test, SOL muscles from sham rats showed a response of 7.12±0.54 N/cm(2) at 60 Hz, which was decreased to 5.45±0.49 N/cm(2) (P<0.05) in MI rats. The contractility of SOL muscles from the MI-LASSBio-294 group was increased to 9.01±0.65 N/cm(2). At 16 mM caffeine, the contractility was reduced from 2.31±0.33 to 1.60±0.21 N/cm(2) (P<0.05) in the MI group. In SOL muscles from MI-LASSBio-294 rats, the caffeine response was increased to 2.62±0.33 N/cm(2). Moreover, SERCA2a expression in SOL muscles was decreased by 0.31-fold (31%) in the MI group compared to the Sham group (P<0.05). In the MI-LASSBio-294 group, it was increased by 1.53-fold (153%) compared to the MI group (P<0.05). Meanwhile, the nuclear density in SOL muscles was increased in the MI group compared to the Sham group. Treatment with LASSBio-294 prevented this enhancement of cellular infiltrate. LASSBio-294 treatment prevented the development of muscular fatigue and improved exercise intolerance in rats submitted to MI.Life sciences 11/2013; · 2.56 Impact Factor
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ABSTRACT: BACKGROUND: The aim of our study was to investigate whether stem cell (SC) therapy with human amniotic fluid stem cells (hAFS, fetal stem cells) and rat adipose tissue stromal vascular fraction cells-GFP positive cells (rSVC-GFP) was able to produce favorable effects on skeletal muscle (SM) remodeling in a well-established rat model of right heart failure (RHF). METHODS: RHF was induced by monocrotaline (MCT) in Sprague-Dawley rats. Three weeks later, four millions of hAFS or rSVC-GFP cells were injected via tail vein. SM remodeling was assessed by Soleus muscle fiber cross sectional area (CSA), myocyte apoptosis, myosin heavy chain (MHC) composition, satellite cells pattern, and SC immunohistochemistry. RESULTS: hAFS and rSVC-GFP injection produced significant SC homing in Soleus (0.68±1.0 and 0.67±0.75% respectively), with a 50% differentiation toward smooth muscle and endothelial cells. Pro-inflammatory cytokines were down regulated to levels similar to those of controls. SC-treated (SCT) rats showed increased CSA (p<0.004 vs MCT) similarly to controls with a reshift toward the slow MHC1 isoform. Apoptosis was significantly decreased (11.12.±8.8cells/mm3 hAFS and 13.1+7.6 rSVC-GFP) (p<0.001 vs MCT) and similar to controls (5.38±3.0cells/mm3). RHF rats showed a dramatic reduction of satellite cells(MCT 0.2±0.06% Pax7 native vs controls 2.60±2.46%, p<0.001), while SCT induced a repopulation of both native and SC derived satellite cells (p<0.005). CONCLUSIONS: SC treatment led to SM remodeling with satellite cell repopulation, decreased atrophy and apoptosis. Modulation of the cytokine milieu might play a crucial pathophysiological role with a possible scenario for autologous transplantation of SC in pts with CHF myopathy.International journal of cardiology 02/2013; · 7.08 Impact Factor
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ABSTRACT: We assessed the time courses of mitochondrial biogenesis factors and respiration in the right ventricle (RV), gastrocnemius (GAS), and left ventricle (LV) in a model of pulmonary-hypertensive rats. Monocrotaline (MT) rats and controls were studied 2 and 4 weeks after injection. Compensated and decompensated heart failure stages were defined according to obvious congestion signs. mRNA expression and protein level of peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α), citrate synthase (CS) mRNA and activity, and mitochondrial respiration were investigated. In addition, mRNA expression of sirtuin1, nuclear respiratory factor 1, and mitochondrial transcription factor A were studied. As early as 2 weeks, the expression of the studied genes was decreased in the MT GAS. At 4 weeks, the MT GAS and MT RV showed decreased mRNA levels whatever the stage of disease, but PGC-1α protein and CS activity were significantly reduced only at the decompensated stage. The functional result was a significant fall in mitochondrial respiration at the decompensated stage in the RV and GAS. The mRNA expression and mitochondrial respiration were not significantly modified in the MT LV. MT rats demonstrated an early decrease in expression of genes involved in mitochondrial biogenesis in a skeletal muscle, whereas reduced protein expression, and the resulting mitochondrial respiratory dysfunction appeared only in rats with overt heart failure, in the GAS and RV. Dissociations between mRNA and protein levels at the compensated stage deserve to be further studied.Molecular and Cellular Biochemistry 10/2012; · 2.33 Impact Factor