Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

Abstract

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.

Hidden Agenda - The Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response in Inflammation-Induced Muscle Wasting

“…In general, protein homeostasis (i.e., proteostasis) in muscle is assured by a critical balance of protein synthesis, quality control and degradation. During muscle atrophy contractile proteins are degraded by the ubiquitin proteasome system (UPS), the autophagy-lysosomal pathway (ALP), and proteases such as calpains and caspases ( 6 ). Briefly, UPS-mediated protein degradation is a sequential process that leads to the degradation of target proteins by a large multiprotease complex called the proteasome.…”

“…As part of protein quality control, the UPS is responsible for the degradation of defective proteins, such as incomplete, misfolded, denatured or oxidized proteins which tend to accumulate and form cytotoxic aggregates. Recently we have eluted on the role and regulation of UPS-dependent protein degradation in ICUAW [for review ( 6 )]. Briefly, UPS-dependent protein degradation is key for many cellular processes, such as cell cycle control, development, signal transduction, and many more.…”

“…Both E3 ligases were also upregulated in the tibialis anterior and gastrocnemius and plantaris of mouse models of neurogenic, inflammation- and starvation induced muscle atrophy ( 28 – 32 ), where their increased expression was associated with the atrophy phenotype and the loss of MyHC. We and others recently summarized the current knowledge about factors and signaling pathways involved in the regulation of E3 ubiquitin ligases relevant for muscle atrophy ( 6 , 33 , 34 ). For this review it is relevant to know that proinflammatory cytokines (e.g., Tumor Necrosis Factor (TNF), Interleukin 6 (IL-6), IL-1β, TNF-Related Weak Inducer of Apoptosis (TWEAK), members of the Transforming Growth Factor (TGFs) family) and acute phase proteins [e.g., Serum Amyloid A1 (SAA1)] are well known factors involved in muscle wasting ( 6 , 33 , 34 ).…”

“…We and others recently summarized the current knowledge about factors and signaling pathways involved in the regulation of E3 ubiquitin ligases relevant for muscle atrophy ( 6 , 33 , 34 ). For this review it is relevant to know that proinflammatory cytokines (e.g., Tumor Necrosis Factor (TNF), Interleukin 6 (IL-6), IL-1β, TNF-Related Weak Inducer of Apoptosis (TWEAK), members of the Transforming Growth Factor (TGFs) family) and acute phase proteins [e.g., Serum Amyloid A1 (SAA1)] are well known factors involved in muscle wasting ( 6 , 33 , 34 ). To cause muscle atrophy, these cytokines bind to their receptors at the myocyte cell surface and activate transcription factors and signaling proteins such as Nuclear Factor-κB (NF-κB), JAK/STAT, SMAD, MAPK, TFEB/TFE3, and IGF/PI3K/AKT to regulate MuRF1/Trim63 and atrogin-1/Fbxo32 expression that in turn mediate muscle atrophy ( 6 , 33 , 34 ).…”

Regulating Proteasome Activity

“…A contribution by Stefanie Haberecht-Müller et al [5] summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases (e.g., atrogin-1 and MuRF) in muscle atrophy and their mode of action on myofibrillar proteins is reported.…”