Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. The protein kinase C (PKC) is activated by free-fatty acids, and its activity is higher in muscle from obese diabetic patients. However, a molecular link between PKC and insulin resistance has not been defined yet. Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. These results provide a novel mechanism linking the activation of PKC to the inhibition of insulin signaling.
"Indeed, extensive evidence demonstrates that accumulation of triacylglycerol (TG) in skeletal muscle is associated with insulin resistance (Perseghin et al., 1999). TG itself directly interfering with insulin action is unlikely, but the general consensus is that accumulation of bioactive lipids, particularly diacylglycerol (DG), causes insulin resistance (Itani et al., 2002; Li et al., 2004; Yu et al., 2002). In addition to being an important metabolic intermediate for TG, DG is a precursor for the synthesis of phospholipids. "
"The toxic lipid metabolites diacylglycerols and ceramides also impair IGF-1/Akt signaling. In skeletal muscle and liver, diacylglycerols activate PKCε and PKCθ, which phosphorylate multiple serine residues of insulin receptor substrate-1 (IRS-1) directly or via JNK and IKKβ ultimately leading to insulin resistance (Yu et al., 2002; Li et al., 2004; reviewed in Samuel et al., 2010; Turban and Hajduch, 2011). Interestingly, PKCθ deletion in dystrophic Dmdmdx mice increases expression of myogenin and myosin heavy chain and decreases necrotic areas in the muscle (Madaro et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Obesity and metabolic disorders such as type 2 diabetes mellitus are accompanied by increased lipid deposition in adipose and non-adipose tissues including liver, pancreas, heart and skeletal muscle. Recent publications report impaired regenerative capacity of skeletal muscle following injury in obese mice. Although muscle regeneration has not been thoroughly studied in obese and type 2 diabetic humans and mechanisms leading to decreased muscle regeneration in obesity remain elusive, the initial findings point to the possibility that muscle satellite cell function is compromised under conditions of lipid overload. Elevated toxic lipid metabolites and increased pro-inflammatory cytokines as well as insulin and leptin resistance that occur in obese animals may contribute to decreased regenerative capacity of skeletal muscle. In addition, obesity-associated alterations in the metabolic state of skeletal muscle fibers and satellite cells may directly impair the potential for satellite cell-mediated repair. Here we discuss recent studies that expand our understanding of how obesity negatively impacts skeletal muscle maintenance and regeneration.
Frontiers in Physiology 12/2013; 4:371. DOI:10.3389/fphys.2013.00371 · 3.53 Impact Factor
"IRS1 signal transduction regulates cell growth and protein synthesis through PI3-kinase/AKT activation and the MAPK cascade involving MEK1/2/ERK signaling [5,6,8,9,38,39]. IRS1 serine phosphorylation of specific residues inhibits downstream signaling by preventing IRS1 tyrosine phosphorylation [4,12,22,40]. Specifically, phosphorylation of serine1095 (referenced as 1101 human numbering) by PKCθ impairs insulin signaling . In support of our hypothesis, PKCθshRNA cells had elevated rates of protein synthesis determined by [3H] phenylalanine incorporation (Figure 3A), accompanied by reduced IRS1 serine1095 phosphorylation following 4 days of differentiation (Figure 3C). "
[Show abstract][Hide abstract] ABSTRACT: Background
Differentiation and fusion of skeletal muscle myoblasts into multi-nucleated myotubes is required for neonatal development and regeneration in adult skeletal muscle. Herein, we report novel findings that protein kinase C theta (PKCθ) regulates myoblast differentiation via phosphorylation of insulin receptor substrate-1 and ERK1/2.
In this study, PKCθ knockdown (PKCθshRNA) myotubes had reduced inhibitory insulin receptor substrate-1 ser1095 phosphorylation, enhanced myoblast differentiation and cell fusion, and increased rates of protein synthesis as determined by [3H] phenylalanine incorporation. Phosphorylation of insulin receptor substrate-1 ser632/635 and extracellular signal-regulated kinase1/2 (ERK1/2) was increased in PKCθshRNA cells, with no change in ERK5 phosphorylation, highlighting a PKCθ-regulated myogenic pathway. Inhibition of PI3-kinase prevented cell differentiation and fusion in control cells, which was attenuated in PKCθshRNA cells. Thus, with reduced PKCθ, differentiation and fusion occur in the absence of PI3-kinase activity. Inhibition of the ERK kinase, MEK1/2, impaired differentiation and cell fusion in control cells. Differentiation was preserved in PKCθshRNA cells treated with a MEK1/2 inhibitor, although cell fusion was blunted, indicating PKCθ regulates differentiation via IRS1 and ERK1/2, and this occurs independently of MEK1/2 activation.
Cellular signaling regulating the myogenic program and protein synthesis are complex and intertwined. These studies suggest that PKCθ regulates myogenic and protein synthetic signaling via the modulation of IRS1and ERK1/2 phosphorylation. Myotubes lacking PKCθ had increased rates of protein synthesis and enhanced myotube development despite reduced activation of the canonical anabolic-signaling pathway. Further investigation of PKCθ regulated signaling may reveal important interactions regulating skeletal muscle health in an insulin resistant state.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.