Signalling Pathways Regulating Protein Turnover in Skeletal Muscle
Introduction
The aim of this review is to assess the current understanding of signalling pathways which regulate protein synthesis and degradation in skeletal muscle. Where possible, information from studies in vivo, intact muscles incubated in vitro and skeletal muscle cell lines will be presented in order to relate conclusions from model systems to the intact animal. With regard to protein synthesis, present knowledge gleaned from investigations in a variety of model systems is such that we have an excellent understanding of the basic process. Consequently, we will limit the discussion to an assessment of the early signalling events involved as this area has been relatively under-explored in skeletal muscle. The role of initiation 1, 2and transcription factors 3, 4, 5will not be discussed in detail as they have been the subject of several recent reviews.
In the case of protein degradation, however, the situation is very different in that little is known with regard to the control mechanisms. We shall therefore present a much broader picture, with an overall view of events, describing the information which is available and highlighting areas which require more detailed investigation.
Section snippets
The Role of Prostaglandins: Studies In Vivo and in Intact Muscle In Vitro
Evidence linking the hydrolysis of membrane phospholipids by the activation of phospholipase A2 (PLA2), with the subsequent release of arachidonic acid (ARA) and the production of prostaglandin F2α (PGF2α) to the control of protein synthesis began to emerge in the early 1980s. These studies suggested that the stimulation of protein synthesis by insulin [6]and the glucocorticoid-induced reduction in rates of protein synthesis [7]were all associated with parallel changes in PGF2α production.
The Role of Protein Degradation and Its Measurement
The control of protein degradation in skeletal muscle is important for energy and protein homeostasis and body growth. In response to fasting, for example, increased proteolysis is essential to provide amino acids for gluconeogenesis and direct oxidation; a response which appears to involve the glucocorticoids and be antagonized by insulin [100]. In many instances, degradation has been measured by determining the release of a single amino acid e.g., tyrosine. However, as this is present in all
Conclusions
Although considerable advances have been made in recent years in the area of signalling pathways and the regulation of protein turnover in skeletal muscle, it is clear that much remains to be investigated. With regard to synthesis, unresolved issues include (1) the mechanism linking PGF2α to the activation of p70s6κ and the phosphorylation of PHAS-1; (2) the involvement or otherwise of MAP kinase (possibly by the use of antisense technology); (3) the role of specific isoforms of PKC,
Acknowledgements
The work reported from this laboratory was sponsored by the Scottish Office Agriculture and Fisheries Department as part of the core budget to the Rowett Research Institute.
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