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.

Aging accentuates alcohol-induced decrease in protein synthesis in gastrocnemius

“…Although our current results confirm these earlier observations, proteasome activity did not differ between control and alcohol-fed rats. These data would suggest that if chronic alcohol intake increases proteolysis in gastrocnemius, the mechanism must be mediated by other pathways for protein breakdown or that the degradation of a relatively small number of specific proteins is enhanced (90).…”

Mechanisms for fiber-type specificity of skeletal muscle atrophy

“…In contrast, type I fibers are more sensitive to inactivity, microgravity, and denervation-induced atrophy [2,3,4 ▪ ], whereas type II fibers are more vulnerable to cancer cachexia, diabetes, chronic heart failure, and aging [1 ▪▪ ,5]. Even though signaling pathways responsible for muscle atrophy have been recently reviewed [6 ▪▪ ,7 ▪▪ ,8 ▪ ], the basis for the selectivity of fiber-type muscle atrophy remains an important and unresolved issue.…”

Systems biology and the integration of mechanistic explanation and mathematical explanation

“…Molecular biologists have come to recognize the importance of this, as witnessed by discussions of 'gene regulatory networks' and the recent terminological shifts from 'metabolic pathway' to 'metabolic network' and from 'signaling pathway' to 'signaling network.' Many researchers emphasize that since there is 'cross-talk' between what deemed to be separate pathways, the larger network needs to be studied (Barabási et al, 2011;Fraser & Germain, 2009;Jørgensen & Linding, 2010;Layek et al, 2011;Wing et al, 2011). Furthermore, the organization of causal interactions is not unidirectional and acyclic, but mechanisms have feedback loops (Bechtel, 2011).…”