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Failure of IGF-1 to affect protein turnover in muscle from growth-retarded neonatal rats
R J Frampton1, H A Jonas, R A MacMahon
1Department of Paediatrics, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.
Insights
Neonatal rats with intrauterine growth restriction exhibit reduced muscle protein synthesis. Insulin-like growth factor-I (IGF-I) fails to stimulate muscle growth in these pups, potentially explaining their impaired catch-up growth.
Area of Science:
- Biochemistry
- Developmental Biology
- Physiology
Background:
- Intrauterine growth restriction (IUGR) leads to impaired neonatal development.
- Insulin-like growth factor-I (IGF-I) plays a crucial role in postnatal growth.
- The response of growth-retarded neonates to IGF-I is not fully understood.
Purpose of the Study:
- To investigate the effect of IGF-I on muscle protein synthesis and degradation in growth-retarded neonatal rats.
- To compare the response to IGF-I in growth-retarded versus control neonatal rat pups.
- To explore the role of IGF-I receptors in mediating these effects.
Main Methods:
- Growth retardation induced in utero by ligation of uterine blood supply.
- In vitro measurement of muscle protein synthesis and degradation rates.
- Assessment of IGF-I, Multiplication Stimulating Activity (MSA), and insulin effects on protein metabolism.
- Characterization of IGF-I receptor binding affinity and concentration.
Main Results:
- Growth-retarded pups showed significantly lower basal muscle protein synthesis compared to controls.
- IGF-I stimulated protein synthesis and inhibited degradation in control pups.
- IGF-I had no significant effect on protein synthesis or degradation in growth-retarded pups.
- IGF-I receptors were present and functional in both groups, with similar affinity and concentration.
Conclusions:
- Growth-retarded neonatal rat muscle is refractory to IGF-I stimulation.
- This refractoriness to IGF-I may contribute to the failure of catch-up growth in IUGR neonates.
- Specific IGF-I receptor characteristics were similar in both groups, suggesting post-receptor signaling defects.
Abstract:
To investigate the response of the growth retarded neonatal rat to insulin-like growth factor-I (IGF-I) we have measured the effect of IGF-I on in vitro muscle protein synthesis and degradation rates in growth retarded and control neonatal rat pups. The growth retarded pups were growth retarded in utero by ligation of the uterine blood supply at day 17 of gestation. Basal levels of muscle protein synthesis in vitro were significantly lower in growth retarded pups compared with controls. Protein degradation rate were not different in muscles taken from the two groups. IGF-I stimulated protein synthesis in muscle from control pups by 12% and 15% at 20 ng/ml and 200ng/ml respectively. Net protein degradation was inhibited by 20% in the presence of 20ng/ml IGF-I. IGF-I had no effect on net protein synthesis or degradation in muscle from growth retarded pups. Neither Multiplication Stimulating Activity (at 20ng/ml or 200ng/ml) nor insulin (at 40ng/ml or 800ng/ml) was able to increase synthesis or decrease degradation of protein. Specific receptors for IGF-I are present on muscle membranes from both groups. Unlabelled IGF-I was more effective than MSA or insulin in competing with 125I-IGF-I for binding to the receptor. The relative affinities are consistent with type I IGF receptors. The affinity of these receptors for IGF-I was similar (Kd approximately 5nM) in both groups and the receptor concentration in both cases was approximately 250 fmol/mg protein. The refractility of tissue from growth retarded pups to IGF-I may be partially responsible for the lack of catch up growth in growth retarded neonates.