CHAPTER 5
Regulation of Muscle Proteostasis via Extramuscular Signals
PHILIP J. ATHERTON* AND NATHANIEL J. SZEWCZYK*
Department of Clinical Physiology, School of Graduate Entry Medicine & Health, Derby, UK, DE22 3DT
5.1 Basic Protein Synthesis
Muscle is a multi-functional tissue, the contractile function of which (i.e. locomotion) is well appreciated. This contractile function requires a substantial protein-based contractile apparatus and catabolism of energy which produces heat. Consequently, in normal healthy humans muscle constitutes the bulk of protein stores and is a major metabolic consumer and producer of heat. Presumably these interrelated functions of muscle have evolved over time such that each has partially independent regulation in various species. Here we consider the regulation of the synthesis and degradation of muscle proteins largely in isolation of the other intertwined functions.
In a normal healthy growth stable animal, protein synthesis and degradation exist in a dynamic equilibrium recently termed proteostasis.1–3 When synthesis and degradation are precisely balanced, no net gain or loss of muscle mass is seen. Conversely if net synthesis exceeds net degradation a gain of mass is observed and if net degradation exceeds net synthesis then a loss of mass is observed. At the fundamental level, proteins are synthesized via translation of mRNA transcripts encoded within DNA based genes. These transcripts are then
RSC Drug Discovery Series No. 10 Extracellular and Intracellular Signaling
Edited by James D. Adams, Jr. and Keith K. Parker r Royal Society of Chemistry 2011
Published by the Royal Society of Chemistry, www.rsc.org
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translated to produce unfolded peptides. The unfolded peptides are then subject to folding, tra cking and/or other post-translational modifications (i.e. glycosylation) to produce functional proteins.
For DNA transcription into mRNA, the bulk of genes are regulated by the binding of transcription factors to DNA elements and to the transcriptional machinery. The proper functioning of the transcriptional machinery is the key regulatory element during elongation, and the key regulatory element of termination appears linked to placing a polyadenylated tail on the mRNA transcript. The regulation of mRNA translation into peptides can be divided into three phases of initiation, elongation and termination. For the bulk of mRNA, initiation of translation involves engaging mRNA bound ribosomes into translation-competent protein/RNA complexes. The final step of translational initiation is regulated via placement of the first amino acid residue by methionyl tRNA. Peptide elongation occurs via delivery of anticodon aminoacyl tRNA to the ribosome and concurrent formation of peptide bonds. Stop codons signal the termination of mRNA translation by facilitating the binding of polypeptide release factor to the ribosome, thereby stimulating hydrolyzing of the final peptidyl transfer RNA linkage and releasing the completed polypeptide from the ribosome. Modulation of protein synthesis can occur at any or all of these stages.
Protein degradation, as we will consider it here, is simply the destruction of functional proteins. Degradation is achieved by cleavage of the peptide bonds that hold the protein together by catabolic enzymes collectively known as proteases. There are four major proteases that are currently considered to contribute to overall maintenance of muscle mass. The first is the proteasome, which degrades proteins that are tra cked to it from elsewhere in the cell via a polyubiquitin carrier system. The proteasome is currently thought to be the major regulator of muscle mass via its role in degradation. However, as it also participates in degrading improperly folded proteins during protein synthesis and at least 30% of bulk peptides do not complete synthesis as we define it here, the proteasome’s role in regulating degradation versus synthesis currently remains open. The second major proteolytic system is the lysosome. Previously the lysosome was thought to be the major regulator of muscle mass via its role in degradation and this belief is currently returning and consistent with the notion that the lysosomal system is the major regulator of cell mass across cell types. Proteins destined for degradation are tra cked via autophagy in the lysosomes membrane enclosed acidic environment. In the case of both proteasomeand lysosome-mediated degradation the likely control points for modulating degradation are at the tra cking step. However, there is also substantial evidence for the regulation of the amount of protease via alterations in synthesis of the proteasome subunits and the lysosomal proteases (i.e. cathepsins). The final two proteases that are believed to contribute to the maintenance of muscle mass are the calpains and the caspases. In both cases these proteases are thought mainly to be regulated at the level of activation of the protease (i.e. cleavage events), which likely explains why both are also thought to have relatively specific and local e ects within muscle. For example, both are thought to participate in disassembly of the complex actinomyosin