Mechanism of induction of muscle protein loss by hyperglycaemia
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK Experimental Cell Research
(Impact Factor: 3.25).
01/2009; 315(1):16-25. DOI: 10.1016/j.yexcr.2008.10.002
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.
Available from: Marco Salomão Fortes
- "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). "
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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.
Available from: Esther E Dupont-Versteegden
- "Moreover, caspase-3 and calpain are both involved in diaphragm muscle atrophy observed during mechanical ventilation (Nelson et al. 2012), and caspase activation is also responsible for muscle wasting induced by the proinflammatory cytokine TWEAK (Bhatnagar et al. 2012). In addition, caspase-8 has been shown to be involved in muscle atrophy in response to high glucose, TNFa and angiotensin II administration, supposedly through the activation of RNA-dependent protein kinase PKR (Eley et al. 2008; Russell et al. 2009). This indicates that caspase-dependent pathways likely play a role in muscle wasting; indeed, inhibition of caspases protects from muscle damage and atrophy (Talbert et al. 2013; Teng et al. 2011). "
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ABSTRACT: Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40-60 % of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and -8 activities, but not caspase-9 and -12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, -27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types.
Available from: Vinicius Fernandes Cruzat
- "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. "
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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.
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