Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks

Abstract

Improvements in health in the past decades have resulted in increased numbers of the elderly in both developed and developing regions of the world. Advances in therapy have also increased the prevalence of patients with chronic and degenerative diseases. Muscle wasting, a feature of most chronic diseases, is prominent in the elderly and contributes to both morbidity and mortality. A major research goal has been to identify the proteolytic system(s) that is responsible for the degradation of proteins that occurs in muscle atrophy. Findings over the past 20 years have clearly confirmed an important role of the ubiquitin proteasome system in mediating muscle proteolysis, particularly that of myofibrillar proteins. However, recent observations have provided evidence that autophagy, calpains and caspases also contribute to the turnover of muscle proteins in catabolic states, and furthermore, that these diverse proteolytic systems interact with each other at various levels. Importantly, a number of intracellular signaling pathways such as the IGF1/AKT, myostatin/Smad, PGC1, cytokine/NFκB, and AMPK pathways are now known to interact and can regulate some of these proteolytic systems in a coordinated manner. A number of loss of function studies have identified promising therapeutic approaches to the prevention and treatment of wasting. However, additional biomarkers and other approaches to improve early identification of patients who would benefit from such treatment need to be developed. The current data suggests a network of interacting proteolytic and signaling pathways in muscle. Future studies are needed to improve understanding of the nature and control of these interactions and how they work to preserve muscle function under various states of growth and atrophy.

Figure 1

The ubiquitin-proteasome system. Conjugation of ubiquitin (Ub) chains to proteins in which each ubiquitin is linked to the other via Lys 48 targets the protein substrate for recognition and degradation by the 26S proteasome. Conjugation is mediated by the sequential action of three enzymes - E1 (ubiquitin activating enzyme), which activates and transfers Ub to E2 (ubiquitin conjugating enzyme), which then works in concert with E3 (ubiquitin protein ligase) to mediate ubiquitination. E3s recognize substrates. The conjugation can also be reversed by deubiquitinating enzymes (DUBs).

Figure 2

Formation of autophagasomes in autophagy. Initiation of the phagaphore can be induced by two signaling complexes–one containing Beclin-1/Vps34 and the other Atg13/ULK1/FIP200. Elongation /maturation of the phagophore is mediated by two protein conjugation pathways–one in which Atg12 becomes conjugated to Atg5 through a pathway mediated by the Atg7 activating enzyme and the Atg10 conjugating enzyme. In the other pathway, LC3 or its paralogs, GABARAP and GATE16, become conjugated to phagophore bound phosphatidylethanolamine through a pathway mediated by the Atg7 activating enzyme, the Atg3 conjugating enzyme and the Atg12-Atg5/Atg16 ligase-like complex.

Figure 3

Signaling pathways involving MAFbx/Atrogin-1 and MuRF-1 that promote muscle wasting. Three major intracellular signaling pathways act to increase muscle protein degradation and suppress synthesis, leading to the loss of mass seen in atrophying muscle. Suppression of signaling through PI3K and AKT, caused by reduced insulin, insulin resistance or reduced IGF1, leads to FoxO translocation to the nucleus and transcription of the atrogenes MAFbx/Atrogin-1 and MuRF-1 as well as activation of autophagy. Myostatin binding to the ActRIIB leads to signaling through Smad intermediates that stimulates FoxO and other downstream targets. Cytokines such as TNF and TWEAK promote NFκB activation and lead to transcriptional activation of atrogenes such as MuRF-1. AMPK activation can augment atrophy signaling through phosphorylation of FoxO while PGC-1α can suppress these pathways also at the level of FoxO. (dashed lines-inhibition; solid lines - stimulation).