Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation

Both proteolysis-inducing factor (PIF) and angiotensin II have been shown to produce a depression in protein synthesis in murine myotubes concomitant with an increased phosphorylation of eukaryotic initiation factor 2 (eIF2α). Both PIF and angiotensin II were shown to induce autophosphorylation of the RNA-dependent protein kinase (PKR), and an inhibitor of this enzyme completely attenuated the depression in protein synthesis and prevented the induction of eIF2α phosphorylation. The PKR inhibitor also completely attenuated the increase in protein degradation induced by PIF and angiotensin II and prevented the increase in proteasome expression and activity. To confirm these results myotubes were transfected with plasmids that express either wild-type PKR, or a catalytically inactive PKR variant, PKRΔ6. Myotubes expressing PKRΔ6 showed no increase in eIF2α phosphorylation in response to PIF or angiotensin II, no depression in protein synthesis, and no increase in protein degradation or increase in proteasome expression. Induction of the ubiquitin-proteasome pathway by PIF and angiotensin II has been linked to activation of the transcription factor nuclear factor-κB (NF-κB). Inhibition of PKR prevented nuclear migration of NF-κB in response to both PIF and angiotensin II, by preventing degradation of the inhibitor protein I-κB. Phosphorylation of PKR and eIF2α was also significantly increased in the gastrocnemius muscle of weight losing mice bearing the MAC16 tumor, suggesting that a similar process may be operative in cancer cachexia. These results provide a link between the depression of protein synthesis in skeletal muscle and the increase in protein degradation. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Changing treaty and changing economic context:the dynamic relationship of the legislature and the judiciary in the pursuit of capital liberalisation

Introduction For a significant period of time (the late 1950s--1980s), a lack of capital freedom was a major obstacle to the progress of the internal market project. The free movements of goods, persons and services were achieved, and developed, primarily through the case law of the Court of Justice of the European Union (CJEU). On the other hand, the Court played a (self-imposed) limited role in the development of the free movement of capital. It was through a progressive series of legislation that the freedom was finally achieved. John Usher has noted that the consequence of this is that ‘free movement of capital thus became the only Treaty “freedom” to be achieved in the manner envisaged in the Treaty’. For this reason, the relationship of the Court and legislature in this area is of particular importance in the broader context of the internal market. The rest of this chapter is split into four sections and will attempt to describe (and account for) the differing relationships between the legislature and the judiciary during the different stages of capital liberalisation. Section 2 will deal with the situation under the original Treaty of Rome. Section 3 will examine a single legislative intervention: Directive 88/361. It was this intervention that contained the obligation for Member States to fully liberalise capital movements. It is therefore the most important contribution to the completion of the internal market in the capital sphere. An examination will be made of whether the interpretation of the Directive demonstrates a changed (or changing attitude) of the Court towards the EU legislature. Section 4 will examine the changes brought about by the Treaty on European Union in 1993. It was at Maastricht that the Member States finally introduced into the Treaty framework an absolute obligation to liberalise capital movements. Finally, Section 5 will consider the Treaty of Lisbon and the possibility of future interventions by the legislature. By looking at the patterns that run through the different parts, this chapter will attempt to engage with the question of whether the approaches were products of their historical context, or whether they can be applied to other areas within the capital movement sphere.