The factors that regulate gene expression of uncoupling proteins 2 and 3 (UCP-2 and UCP-3) in skeletal muscle are poorly understood, but both genes are clearly responsive to the metabolic state of the organism. Therefore, we tested the hypothesis that denervation and acute and/or chronic exercise (factors that profoundly affect metabolism) would alter UCP-2 and UCP-3 gene expression. For the denervation studies, the sciatic nerve of rat and mouse hindlimb was sectioned in one leg while the contralateral limb served as control. Northern blot analysis revealed that denervation was associated with a 331% increase ( P < 0.001) in UCP-3 mRNA and a 200% increase ( P < 0.01) in UCP-2 mRNA levels in rat mixed gastrocnemius (MG) muscle. In contrast, denervation caused a 53% decrease ( P< 0.001) in UCP-3 and a 63% increase ( P < 0.01) in UCP-2 mRNA levels in mouse MG. After acute exercise (2-h treadmill running), rat UCP-3 mRNA levels were elevated (vs. sedentary control) 252% ( P < 0.0001) in white gastrocnemius and 63% ( P < 0.05) in red gastrocnemius muscles, whereas UCP-2 levels were unaffected. To a lesser extent, elevations in UCP-3 mRNA (22%; P < 0.01) and UCP-2 mRNA (55%; P < 0.01) levels were observed after acute exercise in the mouse MG. There were no changes in either UCP-2 or UCP-3 mRNA levels after chronic exercise (9 wk of wheel running). These results indicate that acute exercise and denervation regulate gene expression of skeletal muscle UCPs.
Previous studies have shown that T3 coordinately stimulates GLUT4-glucose transporter messenger RNA (mRNA) and protein expression in mixed fiber-type skeletal muscle of the rat and produces a concomitant elevation in basal (noninsulin mediated) glucose uptake. The aim of the present study was to 1) determine the precise mechanism(s) for the T3-induced expression of GLUT4 in skeletal muscle, and 2) investigate the potential benefits of T3 on noninsulin dependent diabetes mellitus (NIDDM). Ten daily ip injections of T3 (100 micrograms/100 g BW) administered to hypothyroid male Sprague-Dawley rats, increased both GLUT4 mRNA and transcription approximately 70% (P < 0.05) in mixed fiber-type hindlimb skeletal muscle. Transcriptional induction was subsequently defined to be restricted to red (oxidative) muscle fibers (2.5-fold; P < 0.05), whereas GLUT4 protein was increased in both red and white (glycolytic) skeletal muscle. GLUT4 mRNA and protein expression were similarly inducible in the skeletal muscle of insulin-resistant Zucker rats. More importantly, T3 treatment totally ameliorated hyperinsulinemia in obese animals (P < 0.001), although their moderately elevated plasma glucose levels were not significantly altered. In conclusion, regulation of GLUT4 expression by T3 was shown to lie at the transcriptional level in red skeletal muscle, whereas in white muscle fiber types, it appears to operate via an alternative posttranscriptional mechanism. These data also support the potential of hormonally inducing glucose transporter expression in insulin-resistant muscle. However, high levels of T3 are associated with a number of adverse side-effects, in particular the stimulation of hepatic gluconeogenesis. Nevertheless, future studies may demonstrate, e.g. subthyrotoxic levels, to be similarly effective but without side effects, and thus perhaps find a clinical application in reducing both hyperinsulinemia and hyperglycemia in NIDDM.
Transport of glucose across the plasma membrane by GLUT-4 and subsequent phosphorylation of glucose by hexokinase II (HKII) constitute the first two steps of glucose utilization in skeletal muscle. This study was undertaken to determine whether epinephrine and/or insulin regulates in vivo GLUT-4 and HKII gene transcription in rat skeletal muscle. In the first experiment, adrenodemedullated male rats were fasted 24 h and killed in the control condition or after being infused for 1.5 h with epinephrine (30 μg/ml at 1.68 ml/h). In the second experiment, male rats were fasted 24 h and killed after being infused for 2.5 h at 1.68 ml/h with saline or glucose (625 mg/ml) or insulin (39.9 μg/ml) plus glucose (625 mg/ml). Nuclei were isolated from pooled quadriceps, tibialis anterior, and gastrocnemius muscles. Transcriptional run-on analysis indicated that epinephrine infusion decreased GLUT-4 and increased HKII transcription compared with fasted controls. Both glucose and insulin plus glucose infusion induced increases in GLUT-4 and HKII transcription of twofold and three- to fourfold, respectively, compared with saline-infused rats. In conclusion, epinephrine and insulin may regulate GLUT-4 and HKII genes at the level of transcription in rat skeletal muscle.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.