Abstract
Mammalian skeletal muscle expresses GLUT-4 and GLUT-1 glucose transporters. Here, we have investigated whether GLUT-1 and GLUT-4 expression is regulated in muscle by contractile activity. GLUT-1 mRNA levels were high in skeletal muscle at days 16 and 17 of fetal life and decreased markedly by days 19 and 21. In contrast, GLUT-4 mRNA levels were clearly detectable at day 21 of fetal life, and they increased progressively during postnatal life. The timing data for GLUT-4 induction and GLUT-1 repression suggest that these processes are related to skeletal muscle innervation. GLUT-4 mRNA decreased markedly in adult rat and rabbit tibialis anterior muscle after severage of peroneal nerve. In contrast, GLUT-1 mRNA levels showed a 9-fold increase in rat muscle 3 days after denervation. Direct stimulation of rabbit tibialis anterior muscle with extracellular electrodes protected GLUT-4 mRNA levels against the effect of denervation. This indicates that the repression of GLUT-4 mRNA associated with denervation is due, at least in part, to electrical activity. Increased contractile activity induced for 24 h by indirect electrical stimulation at low frequency caused a marked and specific increase in GLUT-1 mRNA levels in rabbit tibialis anterior muscle. Our results indicate that (a) innervation-dependent basal contractile activity regulates in an inverse manner the expression of GLUT-1 and GLUT-4 in skeletal muscle, and (b) enhanced contractile activity stimulates GLUT-1 expression in the absence of modifications to GLUT-4 expression. This suggests the existence of different factors which depend on contractile activity and which control GLUT-1 and GLUT-4 glucose transporter expression in skeletal muscle.
Highlights
To determinewhether glucose transporter levels are regulated by innervation, we analyzed the expressioonf their transcripts during lamteuscle development (16- to 21-day fetuses)
Total RNA was isolated from hindlimbmuscle of 16-21-day fetuses and neonates, and GLUT-4 and GLUT-1 mRspNeAcies were determined by Northern blot.A greater yield of RNA was obtained in skeletal muscle during fetal (3.9 4 0.2 mg/g of tissue)orearlyneonatal life (2.1 0.2 mg/g of tissue) than in the adult state(0.93 f 0.02 mg/g of tissue)
The presenceof GLUT-1 mRNAwas determined by Northern hybridization using a rat cDNA probe under high stringency conditions
Summary
Materials-Hybond N was purchased from Amersham and a random priming DNA labeling kit from Boehringer. At different times after denervation, tibialis anterior muscles were dissected and frozen in liquid nitrogen. In a different set of experiments, stimulation of rabbit tibialis anterior muscle was performed immediately after bilateralsection of the peroneal nerve. 1week before the experiment, electrodes were implanted laterally to the peroneal nerve to induce low frequency stimulation as described elsewhere (Schwarz et al, 1983). This entailed the continuous stimulationin10-Hz trains (trains of pulses of 18 mA for 0.15 ms) for 24 h/day. After a 24-h stimulation period, tibialis anterior muscles were removed and rapidly frozen in liquid nitrogen. The rabbit cDNA probe for GLUT-1 was obtained from Dr Yoshitomo Oka (University of Tokyo). The abundance of specific glucose transporter message was quantified by scanning densitometry (Ultrascan X L enhancer laser densitometer, LKB) of autoradiograms as described above, and data were expressed as a percentage of control values
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