Improved Contractile Function of the mdx Dystrophic Mouse Diaphragm Muscle after Insulin-Like Growth Factor-I Administration

Insulin-like growth factor-I (IGF-1) ameliorates cardiac dysfunction in diabetes although the mechanism of action remains poorly understood. This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity. Adult rat ventricular myocytes were cultured for 8 h with either normal (NG, 5.5 mM) or high (HG, 25.5 mM) glucose, in the presence or absence of IGF-1 (10–500 nM), the PI-3 kinase/Akt inhibitor LY294002 (10 μM), the mTOR inhibitor rapamycin (20 μM) or the calcineurin inhibitors cyclosporin A (5 μM) or FK506 (10 mg/l). Mechanical properties were evaluated using an IonOptix MyoCam system. HG depressed peak shortening (PS), reduced maximal velocity of shortening/relengthening (± dl/dt) and prolongs time-to-90% relengthening (TR90), which were abolished by IGF-1 (100 and 500 nM). Interestingly, the IGF-1-elicited protective effect against HG was nullified by either LY294002 or rapamycin, but not by cyclosporine A or FK506. None of the inhibitors affected cell mechanics. Western blot analysis indicated that HG and IGF-1 stimulated phosphorylation of Akt and mTOR. HG also activated p70s6k and suppressed GSK-3β phosphorylation. However, the HG-induced alterations in phosphorylation of Akt, mTOR, p70s6k and GSK-3β were significantly reversed by IGF-1. Protein expression of Akt, mTOR, p70s6k, GSK-3β, SERCA2a and phospholamban was unaffected by HG, IGF-1 or rapamycin. Rapamycin significantly enhanced Akt phosphorylation whereas it inhibited mTOR phosphorylation. Collectively, our data suggest that IGF-1 may provide cardiac protection against glucose in part through a PI-3 kinase/Akt/mTOR/ p70s6k-dependent and calcineurin-independent pathway.

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Chronic treatment with insulin-like growth factor I enhances myocyte contraction by upregulation of Akt-SERCA2a signaling pathway

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00298.2008 ◽

2008 ◽

Vol 295 (1) ◽

pp. H130-H135 ◽

Cited By ~ 28

Author(s):

Song-Jung Kim ◽

Maha Abdellatif ◽

Sharat Koul ◽

George J. Crystal

Keyword(s):

Growth Factor ◽

Chronic Treatment ◽

Contractile Function ◽

Pi3 Kinase ◽

Signaling Cascade ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Myocyte Function ◽

Growth Factor I

Chronic treatment with insulin-like growth factor I (IGF-I) improves contractile function in congestive heart failure and ischemic cardiomyopathy. The present study investigated the effect of chronic treatment with IGF-I on intrinsic myocyte function and the role of the phosphatidylinositol (PI)3-kinase-Akt-sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signaling cascade in these responses. Myocytes were isolated from 23 adult rats and cultured with and without IGF-I (10−6 M). After 48 h of treatment, myocyte function was evaluated. IGF-I increased contractile function (percent contraction, 7.7 ± 0.3% vs. 4.5 ± 0.3%; P < 0.01) and accelerated relaxation time (time for 70% relengthening, 81 ± 4 vs. 106 ± 5 ms; P < 0.05) compared with untreated myocytes [control (Con)]. The enhanced function was associated with an increase in Ca2+ transients assessed by fura-2 (340/380 nm; IGF-I, 0.42 ± 0.02 vs. Con, 0.25 ± 0.01; P < 0.01). The PI3-kinase inhibitor LY-249002 (10−9 M) abolished the enhanced function caused by IGF-I. IGF-I increased both Akt and SERCA2a protein levels 2.5- and 4.8-fold, respectively, compared with those of Con ( P < 0.01); neither phospholamban nor calsequestrin was affected. To evaluate whether the SERCA2a protein was directly mediated by Akt-SERCA2a signaling, IGF-I-induced changes in the SERCA2a protein were compared in myocytes transfected with adenovirus harboring either constitutively active Akt [multiplicity of infection (MOI), 15] or dominant negative Akt (dnAkt; MOI, 15). The ability of IGF-I to upregulate the SERCA2a protein in myocytes transected with active Akt was absent in dnAkt myocytes. Taken together, our findings indicate that chronic treatment with IGF-I enhances intrinsic myocyte function and that this effect is due to an enhancement in intracellular Ca2+ handling, secondary to the activation of the PI3-kinase-Akt-SERCA2a signaling cascade.

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Insulin-like growth factor I prevents corticosteroid-induced diaphragm muscle atrophy in emphysematous hamsters

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00177.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. R34-R43 ◽

Cited By ~ 30

Author(s):

Mario Fournier ◽

Zhi-Shen Huang ◽

Hongyan Li ◽

Xiaoyu Da ◽

Bojan Cercek ◽

...

Keyword(s):

Growth Factor ◽

Diaphragm Muscle ◽

Constant Infusion ◽

Mrna Levels ◽

Insulin Like Growth Factor ◽

Recombinant Human Insulin ◽

Factor I ◽

Igf I ◽

Fiber Atrophy ◽

Growth Factor I

The aim of this study was to evaluate whether recombinant human insulin-like growth factor I (rhIGF-I) could attenuate or prevent diaphragm (DIA) fiber atrophy with corticosteroid (CS) administration to emphysematous (EMP) hamsters. DIA muscle IGF-I responses to CS administration with and without exogenous rhIGF-I administration were evaluated. Three groups were studied: 1) EMP; 2) EMP + triamcinolone (T; 0.4 mg·kg-1·day-1 im); and 3) EMP + T + IGF-I (600 μg/day by constant infusion). After 4 wk, the DIA was analyzed histochemically and biochemically (IGF-I mRNA levels by RT-PCR and endogenous and exogenous IGF-I peptide levels immunochemically). Body weights of EMP-T progressively decreased, while those of EMP and EMP-T-IGF-I remained stable despite similarly reduced food intake in both T groups. DIA weight was reduced with T but preserved with rhIGF-I infusion. DIA fiber proportions were similar among the groups. The cross-sectional areas of types I, IIa, and IIx fibers were reduced (17 to 31%) with T administration but unchanged with rhIGF-I infusion. DIA IGF-I mRNA levels were similar across all groups. By contrast, the endogenous DIA IGF-I levels were reduced (41%) in the EMP-T-IGF-I animals. Total DIA IGF-I levels (endogenous + exogenous) were still significantly reduced. IGF-I immunoreactivity confirmed this reduction in all DIA fibers. We conclude that DIA fiber atrophy with T was completely prevented by exogenous rhIGF-I administration. This effect was likely mediated by the pharmacological influences of exogenously administered rhIGF-I. We speculate that this results from increased bioavailability of free IGF-I to react with muscle receptors. Reduced endogenous IGF-I levels in the DIA likely reflect a negative-feedback influence. These results may have important clinical implications for treatment options to offset the adverse effects of CS on the respiratory muscles in patients with chronic lung disorders.

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