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: Skeletal muscle phenotype is regulated by a complex interaction between genetic, hormonal, and electrical inputs. However, because of the interrelatedness of these factors in vivo it is difficult to determine the importance of one over the other. Over the last 5 years, we have engineered skeletal muscles in the European Union (EU) and the United States (US) using the same clone of C2C12 cells. Strikingly, the dynamics of contraction of the muscles was dramatically different. Therefore, in this study we sought to determine whether the hormonal milieu (source of fetal bovine serum (FBS)) could alter engineered muscle phenotype. In muscles engineered in serum of US origin time-to-peak tension (2.2-fold), half relaxation (2.6-fold) and fatigue resistance (improved 25%) all showed indications of a shift towards a slower phenotype. Even though there was a dramatic shift in the rate of contraction, myosin heavy chain expression was the same. The contraction speed was instead related to a shift in calcium release/sensitivity proteins (DHPR=3.1-fold lower, slow CSQ=3.4-fold higher, and slow TnT=2.4-fold higher) and calcium uptake proteins (slow SERCA=1.7-fold higher and parvalbumin=41-fold lower). These shifts in calcium dynamics were accompanied by a partial shift in metabolic enzymes, but could not be explained by purported regulators of muscle phenotype. These data suggest that hormonal differences in serum of USDA and EU origin cause a shift in calcium handling resulting in a dramatic change in engineered muscle function. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.Journal of Cellular Biochemistry 08/2014; · 3.06 Impact Factor
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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