Sepsis-induced myopathy

Abstract

Sepsis is a major cause of morbidity and mortality in critically ill patients, and despite advances in management, mortality remains high. In survivors, sepsis increases the risk for the development of persistent acquired weakness syndromes affecting both the respiratory muscles and the limb muscles. This acquired weakness results in prolonged duration of mechanical ventilation, difficulty weaning, functional impairment, exercise limitation, and poor health-related quality of life. Abundant evidence indicates that sepsis induces a myopathy characterized by reductions in muscle force-generating capacity, atrophy (loss of muscle mass), and altered bioenergetics. Sepsis elicits derangements at multiple subcellular sites involved in excitation contraction coupling, such as decreasing membrane excitability, injuring sarcolemmal membranes, altering calcium homeostasis due to effects on the sarcoplasmic reticulum, and disrupting contractile protein interactions. Muscle wasting occurs later and results from increased proteolytic degradation as well as decreased protein synthesis. In addition, sepsis produces marked abnormalities in muscle mitochondrial functional capacity and when severe, these alterations correlate with increased death. The mechanisms leading to sepsis-induced changes in skeletal muscle are linked to excessive localized elaboration of proinflammatory cytokines, marked increases in free-radical generation, and activation of proteolytic pathways that are upstream of the proteasome including caspase and calpain. Emerging data suggest that targeted inhibition of these pathways may alter the evolution and progression of sepsis-induced myopathy and potentially reduce the occurrence of sepsis-mediated acquired weakness syndromes.

Symptoms of Depression in Survivors of Severe Sepsis: A Prospective Cohort Study of Older Americans

“…59,60 If functional impairment is a cause of depression following severe sepsis, then efforts targeting early physical and cognitive rehabilitation in the intensive care unit, which have been shown to improve functional outcomes at hospital discharge, 61 could prevent the development of subsequent depression. Furthermore, since premorbid depression appears to convey considerable risk for substantial symptoms of depression in the aftermath of severe sepsis, hospital programs that target older patients surviving severe sepsis with a prior history of depression—whether or not formally diagnosed—for careful monitoring of their subsequent mental health may improve outcomes.…”

Insulin Control of Blood Glucose and GLUT4 Expression in the Skeletal Muscle of Septic Rats

“…Myocytolysis was also noticed in septic skeletal muscle. The mechanisms leading to sepsis-induced changes in skeletal muscle are linked to excessive localized elaboration of pro-inflammatory cytokines, marked increases in free-radical generation, and activation of proteolytic pathways (22,23). Muscle protein degraded through the activation of ubiquitin-proteasome pathway after decrease in PI3-K activation (24).…”

Skeletal Muscle Dysfunction in Critical Illness

“…Muscle proteins break down into amino acids and some are used in the liver for the synthesis of glutathione and acute proteins. Muscle proteins to be degraded are derived from myofibrillar proteins (actin, myosin), which account for 60-70% of muscle proteins [56]. Therefore, stressed patients lose 250 g/day of muscle protein corresponding to a muscle mass between 750 and 1000 g [57].…”

“…Inflammatory cytokines [tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-1β] and complement factors (C3a and C5a) act as important mediators at this stage of inflammation [54]. Inflammatory stimulation causes muscle wasting mainly by degradation of muscle proteins [56]. Muscle proteins break down into amino acids and some are used in the liver for the synthesis of glutathione and acute proteins.…”