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

Abstract

Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.

N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress

“…Inflammation is considered to be the major predisposing factor for skeletal muscle atrophy, which disturbs the homeostasis of the ER [42,43]. Notably, ER stress also affects the inflammatory process in turn [30]. Therefore, we examined ER stress levels in septic mice and LPS-induced myotubes after NAC treatment and found that ER stress biomarkers followed the same trend as Atrogin-1 and MuRF1, with NAC decreasing their expression levels.…”

“…PERK is activated by auto-phosphorylation as well, leading to a cascade of signals, including the activation of eIF2α and CHOP. The PERK/eIF2α signaling axis also induces the expression of GADD34 [30,31]. Initially, we found that sepsis induces the expression of GRP78, IRE1, sXBP1, eIF2α, GADD34, and CHOP.…”

Predictive modeling of ICU-AW inflammatory factors based on machine learning

“…ICU-AW is associated with multiple risk factors such as sepsis, multiple organ system failure, systemic in ammation, prolonged sedation, prolonged mechanical ventilation, prolonged immobilization, hyperglycemia, glucocorticoids, and neuromuscular blocking agents (17,18) . Critically ill patients with ICU-AW may experience a prolonged decline in quality of life after discharge from the hospital, including di culty swallowing, inability to maintain an upright posture, and physical weakness that lasts for months or even years (19,20) . ICU-AW may result in higher rehab care costs per patient (21) .Consider multiple diagnostic methods for ICU-AW, including muscle biopsy, MRC scale, electromyography, and muscle ultrasound.…”

Integrated analysis of multi-omics data reveals T cell exhaustion in sepsis

“…In severe sepsis, protein breakdown occurs in skeletal muscle, leading to malnutrition in the body, as well as respiratory muscle dysfunction and pulmonary complications. This process is mainly involved in the ubiquitin-proteasome protein degradation pathway ( 22 ). This is consistent with the proteasome up-regulation identified here.…”