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Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat.

ABSTRACT: Recent data have suggested that insulin resistance may be associated with a diminished ability of skeletal muscle to undergo hypertrophy (Paturi S, Gutta AK, Kakarla SK, Katta A, Arnold EC, Wu M, Rice KM, Blough ER. J Appl Physiol 108: 7-13, 2010). Here we examine the effects of insulin resistance using the obese Zucker (OZ) rat with increased muscle loading on the regulation of the mammalian target of rapamycin (mTOR) and its downstream signaling intermediates 70-kDa ribosomal protein S6 kinase (p70S6k), ribosomal protein S6 (rpS6), eukaryotic elongation factor 2 (eEF2), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Compared with that observed in lean Zucker (LZ) rats, the degree of soleus muscle hypertrophy as assessed by changes in muscle wet weight (LZ: 35% vs. OZ: 16%) was significantly less in the OZ rats after 3 wk of muscle overload (P < 0.05). This diminished growth in the OZ rats was accompanied by significant impairments in the ability of the soleus to undergo phosphorylation of mTOR (Ser(2448)), p70S6k (Thr(389)), rpS6 (Ser(235/236)), and protein kinase B (Akt) (Ser(473) and Thr(308)) (P < 0.05). Taken together, these data suggest that impaired overload-induced hypertrophy in insulin-resistant skeletal muscle may be related to decreases in the ability of the muscle to undergo mTOR-related signaling.

SUBMITTER: Katta A

PROVIDER: S-EPMC3007193 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat.

Katta Anjaiah A Kundla Sudarsanam S Kakarla Sunil K SK Wu Miaozong M Fannin Jacqueline J Paturi Satyanarayana S Liu Hua H Addagarla Hari S HS Blough Eric R ER

American journal of physiology. Regulatory, integrative and comparative physiology 20101006 6

Recent data have suggested that insulin resistance may be associated with a diminished ability of skeletal muscle to undergo hypertrophy (Paturi S, Gutta AK, Kakarla SK, Katta A, Arnold EC, Wu M, Rice KM, Blough ER. J Appl Physiol 108: 7-13, 2010). Here we examine the effects of insulin resistance using the obese Zucker (OZ) rat with increased muscle loading on the regulation of the mammalian target of rapamycin (mTOR) and its downstream signaling intermediates 70-kDa ribosomal protein S6 kinase ...[more]

PMID: 20926758

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Project description:Obesity plays an important role in the pathogenesis of hypertension. Renal dopamine D1-like receptor-mediated diuresis and natriuresis are impaired in the obese Zucker rat, an obesity-related hypertensive rat model. The role of arterial D1 receptors in the hypertension of obese Zucker rats is not clear.Plasma glucose and insulin concentrations and blood pressure were measured. The vasodilatory response of isolated mesenteric arteries was evaluated using a small vessel myograph. The expression and phosphorylation of D1 receptors were quantified by co-immunoprecipitation and immunoblotting To determine the effect of hyperinsulinemia and hyperglycemia on the function of the arterial D1 receptor, we studied obese Zucker rats (six to eight-weeks old) fed (6 weeks) vehicle or rosiglitazone, an insulin sensitizer (10 mg/kg per day) and lean Zucker rats (eight to ten-weeks old), fed high-fat diet to induce hyperinsulinemia or injected intraperitoneally with streptomycin (STZ) to induce hyperglycemia.In obese Zucker rats, the vasorelaxant effect of D1-like receptors was impaired that could be ascribed to decreased arterial D1 receptor expression and increased D1 receptor phosphorylation. In these obese rats, rosiglitazone normalized the arterial D1 receptor expression and phosphorylation and improved the D1-like receptor-mediated vasorelaxation. We also found that D1 receptor-dependent vasorelaxation was decreased in lean Zucker rats with hyperinsulinemia or hyperglycemia but the D1 receptor dysfunction was greater in the former than in the latter group. The ability of insulin and glucose to decrease D1 receptor expression and increase its phosphorylation were confirmed in studies of rat aortic smooth muscle cells.Both hyperinsulinemia and hyperglycemia caused D1 receptor dysfunction by decreasing arterial D1 receptor expression and increasing D1 receptor phosphorylation. Impaired D1 receptor-mediated vasorelaxation is involved in the pathogenesis of obesity-related hypertension.

Project description:New findingsWhat is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus.AbstractDivergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non-overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. -6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between-group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

Dataset Information

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat.

Publications

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat.

Similar Datasets

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