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.
"Furthermore, IGF-I Ea induces influx of calcium into the cytoplasm via L-type Ca 2? channels (Delbono et al. 1997) (see ''Intracellular calcium'') and is involved in recruitment of satellite cells, either independently or in combination with other growth factors such as basic fibroblast growth factor (bFGF) or hepatocyte growth factor (HGF) and MGF (Allen and Boxhorn 1989; Doumit et al. 1993; Yang and Goldspink 2002). In addition, IGF-I also acts as an inhibitor of degradation via inhibition of the FOXO–E3 ligase–proteasome and attenuating caspasesmediated apoptosis (Bodine et al. 2001b; Dalla Libera et al. 2004). These results suggest that IGF-I signaling is important for mediating increases in the capacity for protein accumulation in response to mechanical loading. "
"In fact inflammation by itself is able to produce ubiquitindependent wastage, alteration of AKT-FOXO signaling with inadequate growth , apoptosis  and impaired regeneration [10,11]. These physiopathological conditions can be modified by treatment with ACEIs or ARBs  , physical training  and drugs able to block pro-apoptotic signaling   . "
[Show abstract][Hide abstract] 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).
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.
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.± 8.8 cells/mm(3) hAFS and 13.1+7.6 rSVC-GFP) (p<0.001 vs MCT) and similar to controls (5.38 ± 3.0 cells/mm(3)). 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).
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; 168(3). DOI:10.1016/j.ijcard.2013.01.168 · 4.04 Impact Factor
"Because the gain and loss of functions of GH in embryos cause developmental defects, GH is thought to play a vital role in embryogenesis. GH participates in embryonic development as a growth and differentiation factor, and in cell proliferation as an antiapoptotic factor and in meiotic progression [19,20]. Instead of pituitary GH, maternal or local GH takes part in regulating early embryogenesis via paracrine/autocrine effects, since GH and its receptors exist prior to the formation of functional pituitary somatotrophs [21,22]. "
[Show abstract][Hide abstract] ABSTRACT: Dysmorphogenesis and multiple organ defects are well known in zebrafish (Danio rerio) embryos with T-box transcription factor 5 (tbx5) deficiencies, mimicking human Holt-Oram syndrome.
Using an oligonucleotide-based microarray analysis to study the expression of special genes in tbx5 morphants, we demonstrated that GH and some GH-related genes were markedly downregulated. Zebrafish embryos microinjected with tbx5-morpholino (MO) antisense RNA and mismatched antisense RNA in the 1-cell stage served as controls, while zebrafish embryos co-injected with exogenous growth hormone (GH) concomitant with tbx5-MO comprised the treatment group.
The attenuating effects of GH in tbx5-MO knockdown embryos were quantified and observed at 24, 30, 48, 72, and 96 h post-fertilization. Though the understanding of mechanisms involving GH in the tbx5 functioning complex is limited, exogenous GH supplied to tbx5 knockdown zebrafish embryos is able to enhance the expression of downstream mediators in the GH and insulin-like growth factor (IGF)-1 pathway, including igf1, ghra, and ghrb, and signal transductors (erk1, akt2), and eventually to correct dysmorphogenesis in various organs including the heart and pectoral fins. Supplementary GH also reduced apoptosis as determined by a TUNEL assay and decreased the expression of apoptosis-related genes and proteins (bcl2 and bad) according to semiquantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis, respectively, as well as improving cell cycle-related genes (p27 and cdk2) and cardiomyogenetic genes (amhc, vmhc, and cmlc2).
Based on our results, tbx5 knockdown causes a pseudo GH deficiency in zebrafish during early embryonic stages, and supplementation of exogenous GH can partially restore dysmorphogenesis, apoptosis, cell growth inhibition, and abnormal cardiomyogenesis in tbx5 knockdown zebrafish in a paracrine manner.
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