Mechanism of induction of muscle protein loss by hyperglycaemia
ABSTRACT Treatment of murine myotubes with high glucose concentrations (10 and 25 mM) stimulated protein degradation through the ubiquitin–proteasome pathway, and also caused activation (autophosphorylation) of PKR (double-stranded-RNA-dependent protein kinase) and eIF2α (eukaryotic initiation factor 2α). Phosphorylation of PKR and eIF2α was also seen in the gastrocnemius muscle of diabetic ob/ob mice. High glucose levels also inhibited protein synthesis. The effect of glucose on protein synthesis and degradation was not seen in myotubes transfected with a catalytically inactive variant (PKRΔ6). High glucose also induced an increased activity of both caspase-3 and -8, which led to activation of PKR, since this was completely attenuated by the specific caspase inhibitors. Activation of PKR also led to activation of p38MAPK (mitogen activated protein kinase), leading to ROS (reactive oxygen species) formation, since this was attenuated by the specific p38MAPK inhibitor SB203580. ROS formation was important in protein degradation, since it was completely attenuated by the antioxidant butylated hydroxytoluene. These results suggest that high glucose induces muscle atrophy through the caspase-3/-8 induced activation of PKR, leading to phosphorylation of eIF2α and depression of protein synthesis, together with PKR-mediated ROS production, through p38MAPK and increased protein degradation.
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- "These animals also display a short-term increase in the proteolytic activity in the soleus and extensor digitorum longus (EDL) muscles 1–3 days after entering into the diabetic state returning to control levels after 5 days (Pepato et al. 1996). Hyperglycemia has been associated to reduced skeletal muscle mass (Oku et al. 2001; Russell et al. 2009) and in long-term leads to increased production of reactive oxygen species (ROS) and of advanced glycation end products (AGEs) that exacerbate the loss of skeletal muscle mass (Baynes 1991; Riboulet-chavey et al. 2006; Grzelkowska-Kowalczyk et al. 2013). "
ABSTRACT: The aim of this study was to evaluate the effect of overload-induced hypertrophy on extensor digitorum longus (EDL) and soleus muscles of streptozotocin-induced diabetic rats. The overload-induced hypertrophy and absolute tetanic and twitch forces increases in EDL and soleus muscles were not different between diabetic and control rats. Phospho-Akt and rpS6 contents were increased in EDL muscle after 7 days of overload and returned to the pre-overload values after 30 days. In the soleus muscle, the contents of total and phospho-Akt and total rpS6 were increased in both groups after 7 days. The contents of total Akt in controls and total rpS6 and phospho-Akt in the diabetic rats remained increased after 30 days. mRNA expression after 7 days of overload in the EDL muscle of control and diabetic animals showed an increase in MGF and follistatin and a decrease in myostatin and Axin2. The expression of FAK was increased and of MuRF-1 and atrogin-1 decreased only in the control group, whereas Ankrd2 expression was enhanced only in diabetic rats. In the soleus muscle caused similar changes in both groups: increase in FAK and MGF and decrease in Wnt7a, MuRF-1, atrogin-1, and myostatin. Differences between groups were observed only in the increased expression of follistatin in diabetic animals and decreased Ankrd2 expression in the control group. So, insulin deficiency does not impair the overload-induced hypertrophic response in soleus and EDL muscles. However, different mechanisms seem to be involved in the comparable hypertrophic responses of skeletal muscle in control and diabetic animals. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.07/2015; 3(7):16. DOI:10.14814/phy2.12457
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- "A variety of muscle cell functions can be altered by chemical and mechanical stimuli, establishing a cause and effect in relation to glucose homoeostasis and insulin signalling (Newsholme et al. 2012a). In both T1DM and T2DM, skeletal muscle cells show an imbalance between protein synthesis and degradation, resulting in increased myofibrillar protein breakdown and muscle wasting (Russell et al. 2009), with a concomitant increase in glycated end products and vascular complications (Newsholme et al. 2011, Krause et al. 2012). Once released by pancreatic b-cells into the circulation, insulin initiates its anabolic effects through binding of the transmembrane insulin receptor (IR) in target tissues. "
ABSTRACT: Pancreatic β-cell function is of critical importance in the regulation of fuel homeostasis, and metabolic dysregulation is a hallmark of diabetes mellitus (DM). The β-cell is an intricately designed cell type that couples metabolism of dietary sources of carbohydrates, amino acids, and lipids to insulin secretory mechanisms, such that insulin release occurs at appropriate times to ensure efficient nutrient uptake and storage by target tissues. However, chronic exposure to high nutrient concentrations results in altered metabolism that impacts negatively on insulin exocytosis, insulin action, and may ultimately lead to development of DM. Reduced action of insulin in target tissues is associated with impairment of insulin signalling and contributes to insulin resistance (IR), a condition often associated with obesity, and a major risk factor for DM. The altered metabolism of nutrients by insulin sensitive target tissues (muscle, adipose, and liver) can result in high circulating levels of glucose and various lipids, which further impact on pancreatic β-cell function, IR, and progression of the metabolic syndrome. Here, we have considered the role played by the major nutrient groups, carbohydrates, amino acids, and lipids, in mediating β-cell insulin secretion, while also exploring the interplay between amino acids and insulin action in muscle. We also focus on the effects of altered lipid metabolism in adipose and liver resulting from activation of inflammatory processes commonly observed in DM pathophysiology. The aim of this review is to describe commonalities and differences in metabolism related to insulin secretion and action, pertinent to the development of DM.Journal of Endocrinology 03/2014; 221(3). DOI:10.1530/JOE-13-0616 · 3.59 Impact Factor
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- "In addition, PKC activation closely associates with insulin resistance in skeletal muscle (Schmitz-Peiffer and Biden, 2008). Apoptosis has a role in muscle homeostasis and is associated with diabetic-related muscle atrophy (Wang et al., 2006; Russell et al., 2009; Sishi et al., 2011). Caspase-3 and Fas are up-regulated in the myocardium of an insulin-resistant diabetic rat model suggesting the muscle was in a pre-apoptotic state (Ares-Carrasco et al., 2009). "
ABSTRACT: This study investigated the potential mechanisms that may underlie diabetes induced amyoatrophy. Sprague-Dawley rats were either injected intraperiotneally with STZ (test group; N=8) to induce diabetic-like symptoms (blood glucose level ≥16.65mmol/L) or with buffer (control group; N=8). Differences in muscle structure between the STZ-induced diabetic and control groups were evaluated by histochemistry. Protein and mRNA levels of basic FGF (bFGF), bax, bcl-2, and caspase 3 in skeletal muscle were compared between the 2 groups using immunohistochemistry and quantitative PCR, respectively. Serum level of insulin and protein kinase C (PKC) were measured by competitive RIA and ELISA, respectively. Unlike control animals, the skeletal muscle fibers from STZ-induced diabetic animals were broken and pyknotic, the sarcomeric structure disrupted, and mild hyperplasia of interstitial adipose tissues was detected. The serum level of PKC was higher (P=0.003) and the protein and mRNA levels of bFGF in skeletal muscle were lower (P=0.001) in STZ-induced diabetic versus control animals. Protein and mRNA levels of the apoptosis promoting genes caspase-3 and bax were higher in skeletal muscle from STZ-induced diabetic rats as compared to control animals (P<0.001 and P=0.037, respectively), while mRNA and protein levels of bcl-2, an inhibitor of apoptosis, was lower in STZ-induced diabetic rats versus control animals (P=0.026). Increasing apoptosis in skeletal muscle from STZ-induced diabetic rats was further demonstrated by TNNEL assay. Our findings suggest that enhanced PKC levels, reduction of bFGF expression, and increased in apoptosis might be associated with the development of diabetes-induced myoatrophy.Tissue and Cell 09/2013; DOI:10.1016/j.tice.2013.07.008 · 1.05 Impact Factor